Abstract
Hepatocellular carcinoma (HCC) is responsible for roughly 90% of all cases of primary liver cancer, and the cases are on the rise. The treatment of advanced HCC is a serious challenge. Immune checkpoint inhibitor (ICI) therapy has marked a watershed moment in the history of HCC systemic treatment. Atezolizumab in combination with bevacizumab has been approved as a first-line treatment for advanced HCC since 2020; however, the combination therapy is only effective in a limited percentage of patients. Considering that the tumor immune microenvironment (TIME) has a great impact on immunotherapies for HCC, an in-depth understanding of the immune landscape in tumors and the current immunotherapeutic approaches is extremely necessary. We elaborate on the features, functions, and cross talk of the innate and adaptive immune cells in HCC and highlight the benefits and drawbacks of various immunotherapies for advanced HCC, as well as future projections. HCC consists of a heterogeneous group of cancers with distinct etiologies and immune microenvironments. Almost all the components of innate and adaptive immune cells in HCC have altered, showing a decreasing trend in the number of tumor suppressor cells and an increasing trend in the pro-cancer cells, and there is also cross talk between various cell types. Various immunotherapies for HCC have also shown promising efficacy and application prospect. There are multilayered interwoven webs among various immune cell types in HCC, and emerging evidence demonstrates the promising prospect of immunotherapeutic approaches for HCC.
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Introduction
The liver is a vital hub of macronutrient metabolism, lipid homeostasis, detoxification, and immune surveillance. In addition to its tolerance property toward antigens that are commonly encountered, the liver is an immune-active organ because of its responsibility to remove pathogens and gut-draining antigens from the systemic circulation. A healthy liver is primarily populated by leukocytes, including Kupffer cells (KCs), T cells, B cells, natural killer (NK) cells, and NKT cells [1, 2]. The tolerogenic and immune-rich environment of the liver maintains local and systemic homeostasis. Once the liver cancer has developed, the tolerogenic environment promotes tumor progression [3].
Hepatocellular carcinoma (HCC) is responsible for roughly 90% of all cases of primary liver cancer. Chronic hepatitis virus infections, alcohol misuse, metabolic syndrome, and several monogenic diseases are well-known risk factors for HCC. Most patients are diagnosed with HCC at an advanced stage since the disease is almost symptomless in the early stages. Advanced HCC used to be treated with transarterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs), but these modalities do not significantly prolong the lifespan of patients [4]. However, immunotherapies are transforming cancer treatment [5]. Nivolumab and pembrolizumab, both anti-PD-1 drugs, have been used as second-line treatments for advanced HCC resistant to sorafenib [6, 7]. When compared to first-line sorafenib, the combination of atezolizumab (an anti-PD-L1) and bevacizumab (a VEGF blockade) provides superior outcomes and has become a new first-line treatment in advanced HCC [5]. Despite a significant paradigm shift in HCC treatment, immunotherapies still have limitations due to a lack of data on drug resistance and response prediction. Previous research has suggested that the tumor immune microenvironment (TIME) of HCC is significantly related to the prognosis and treatment response [8, 9]. This review summarizes the immunobiological features of HCC, with a focus on various innate and adaptive immune cells (shown in Fig. 1) in the tumor microenvironment (TME) and the cross talk among them. We also describe recent immunotherapeutic approaches and potential future directions.
Innate immune cells in HCC
Myeloid cells
Dendritic cells
Like dendritic cells (DCs) in other tissues, liver DCs mainly include conventional DCs (cDCs) and plasmacytoid DCs (pDCs) [10]. cDCs are the only cells in the body capable of activating naive T cells, whereas pDCs are inefficient antigen-presenting cells in the liver [11, 12].
In HCC, the proportion of LAMP3 + DCs that originated from cDC1 or cDC2 and are correlated with the malfunction of T lymphocytes is higher in tumor tissues than that in adjacent non-tumor tissues, and the fraction of pDCs in relapsed tumor samples is larger than that in primary tumor samples [13, 14]. Hypoxia is a common phenomenon in tumors. In severely hypoxic tumor regions of HCC, regulatory T cells (Tregs) and cDC2 can be attracted by CCL20 and CXCL5, and hepatoma cell-derived extracellular adenosine can recruit pDCs via the hypoxia-inducible factor (HIF)-1α/CD39/CD73 signaling pathway [15, 16]. HCC-produced α-fetoprotein (AFP) can impair biological metabolism of DCs by suppressing the expression of the metabolism regulators SREBP-1 and PGC1-α, mediate the dysfunction and apoptosis of DCs, and suppress the activation of NK cells by DCs [17,18,19]. In addition, in an in vitro study, tumor culture supernatants from HCC cell lines could impede the differentiation and maturation of monocyte-derived DCs, leading them to develop an immunosuppressive interleukin (IL)-10highIL-12lowTNF-αlow cellular phenotype [20]. Tumor-associated DCs can induce tumor immune evasion via suppressing the functions of various T cell subsets and NK cells through multiple ligand-receptor pairs, including PD-1/PD-L1, and promoting the expansion of Tregs, which can mediate the loss of HLA-DR from DCs to maintain their tumor immunosuppressive activity, forming a positive feedback loop [13, 15, 16].
Neutrophils
Neutrophils are rich in the peripheral blood. The abundance of neutrophils depends on continuous supplementation through granulopoiesis in the bone marrow because of the limited lifespan of these cells. Neutrophils exhibit a strong effector response when they are recruited into inflammation sites [21]. In the past few decades, neutrophils have been regarded as a unique component that can promote the intercellular communication between tumor cells and TME [22]. Tumor-associated neutrophils (TANs) were confirmed to have different activation/differentiation states, including the N1 phenotype (anti-tumor) and the N2 phenotype (pro-tumor) [23]. N1 TANs have enhanced phagocytosis and migratory capacity, increased oxidative burst, and enhanced cytotoxicity for tumor cells. N2 TANs have inhibitory effects on T cells and are less cytotoxic to tumor cells [24].
In HCC, monocyte-derived CXCL2 and CXCL8 can recruit peripheral neutrophils to TME and sustain their survival [25], and tumor cells then educate the peripheral blood neutrophils to develop into CCL2 + or CCL17 + TANs via PI3K/Akt and p38/MAPK signaling pathways. As a result, TANs are distributed all over the tumor stroma. TANs can facilitate neovascularization and progression of HCC by the recruitment of macrophages and Tregs, which is related to the poor prognosis of HCC [26]. Activated neutrophils can form extracellular traps (NETs) under various inflammatory conditions [27]. NET formation is increased in HCC-derived neutrophils. The increased NETs can inhibit HCC cell death and enhance the invasiveness of HCC cells via activation of TLR4/9-COX2 signaling [28]. Furthermore, cortisol, which is mainly produced in males, can induce TGF-β expression in the liver, TGF-β is associated with TAN recruitment and the upregulation of some pro-tumor molecules, contributing to the gender disparity in HCC carcinogenesis [29]. Moreover, cancer stem cell-like cells (CSCs) have been confirmed to exist in various cancers, including HCC. CSCs are linked to the development and progression of HCC [30, 31]. TANs can increase the stem cell properties in tumor cells via the miR-301b-3p/LASMP/CYLD signaling pathway, and liver CSCs can recruit more TANs into the TME by secreting high levels of CXCL5 because of the hyperactive NF-κB signaling. It is a positive feedback loop, ultimately fostering HCC progression [32]. A latest study found that cabozantinib (a TKI) combined with anti-PD-1 can promote the recruitment of N1 TANs in HCC and inhibit tumor progression [33]. Recently, some TAN-targeting drugs have undergone clinical testing and demonstrated some therapeutic benefits [34,35,36]. However, more investigation is required to ascertain the function of neutrophil phenotypes, particularly TAN phenotypes, in HCC.
Kupffer cells
KCs, which line the liver sinusoids, are the liver-resident macrophages. KCs are responsible for detoxifying blood that may contain harmful enteric pathogens or toxic digestive byproducts, as well as being involved in inflammatory processes, particularly in viral hepatitis and HCC [37]. There are two functionally opposite phenotypes of KCs in the healthy liver: classically (M1) and alternatively (M2) activated KCs, with a balance between them [38]. Besides KCs, there is another macrophage subtype in the liver, peripheral blood monocyte-derived macrophages (MoMFs) [39].
Even though KCs are the first line of defense against HCC cells, most studies have confirmed their pro-cancer roles in HCC, and TME-driven KC transition from M1 to M2 may be one important cause [38, 40, 41]. In mouse HCC tissues, myeloid-derived suppressor cells (MDSCs), an immunosuppressive cell, could inhibit the costimulatory molecule expression and the antigen-presenting function of KCs while increasing the expression of coinhibitory molecules in KCs, which could be another cause of the cancer-promoting KC formation [40]. In an HCC mouse model, M2-KCs were thought to be a key factor in tumor progression, and microRNA-206, which could promote M1-KC polarization, had been shown to increase the percentage of CD8 + T cells in HCC and suppress tumor growth [38]. Furthermore, based on a recent study, different types of TMEs were present in HCC, with distinct cell distribution patterns corresponding to different stages of hepatocyte dedifferentiation. The regional immunity of HCC was reversely regulated by KCs and infiltrating MoMFs with pro- and anti-tumor functions, respectively. In HCC mouse models, KC depletion could increase the intratumoral infiltration of MoMFs and improve the efficacy of anti-PD-1 antibodies, inhibiting tumor progression [41]. Mechanistically, KCs can suppress the tumor-killing toxicity of CD8 + T cells via B7-H1/PD-1 interactions or mucin domain-containing molecule-3 (Tim-3)/galectin-9 signaling pathways in HCC [42, 43]. In addition, KCs also play an important role in hepatocarcinogenesis [44,45,46]. Sympathetic nervous system-mediated activation of KCs, as well as autophagy-deficient KCs, can promote the tumorigenesis of HCC by increasing liver inflammation and fibrosis [44, 45]. TREM-1 (triggering receptor expressed on myeloid cells), the proinflammatory receptor on KCs, can also regulate the activation of KCs and the development of HCC [46].
Myeloid-derived suppressor cells
MDSCs exert immunosuppressive roles by releasing large quantities of active components [47]. Two major MDSC subpopulations, monocyte MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs), were recently identified. Another subtype is early MDSCs (eMDSCs), which contain more progenitor cells that can differentiate into mature MDSCs [48]. In different conditions of TME, MDSCs may transform into DCs, neutrophils, or macrophages and conduct a variety of functions [49].
MDSCs are increased in the peripheral blood and tumor tissues of HCC patients, and the number of PMN-MDSCs in the peripheral blood exceeds that of M-MDSCs, which is associated with poor prognosis [50,51,52,53,54,55,56]. Hepatic stellate cells (HSCs), non-parenchymal hepatocytes, are activated when the liver is injured [57]. In HCC, activated HSCs can recruit MDSCs by producing the stromal cell-derived factor 1 and induce MDSC expansion via IL-6 signaling or the complement C3 pathway [58,59,60]. Cancer-associated fibroblasts (CAFs), which originate from HSCs, play pro-tumorigenic roles through their interaction with HCC cells, and CAF-derived cytokines can stimulate the generation of MDSCs [61, 62]. Furthermore, HIF-1 can promote MDSC accumulation via ectonucleoside triphosphate diphosphohydrolase-2, which can also inhibit MDSC maturation in HCC [63, 64]. In addition, chronic restraint stress-related β-adrenergic signaling in HCC can also recruit MDSCs through the CXCL5-CXCR2-Erk signaling pathway [65]. MDSCs can promote tumor progression via multiple pathways. MDSC-derived IL-10 has been shown to inhibit IL-12 production and DC activation, and MDSC-derived fibroblast growth factor 1 has been shown to activate CAFs, resulting in tumor growth [66, 67]. Moreover, M-MDSCs can suppress tumor immunity via the CXCL10/TLR4/MMP14 signaling, thereby increasing tumor recurrence after liver transplantation [68]. Endoplasmic reticulum (ER) stress, characterized by the accumulation of a large amount of structurally abnormal protein in the ER and the subsequent aberrant response, is confirmed to be associated with hepatocarcinogenesis [69, 70]. The increased PMN-MDSCs in HCC can impede T cell proliferation through the ROS/Arginase I pathway, which is mediated by ER stress [71].
Mast cells
Human mast cells (MCs) originate from hematopoietic stem cells. Mature MCs are observed in almost all tissues as hypergranular cells but are absent in blood. MCs can be classified into several subpopulations based on their properties. According to their tissue localization, MCs can be divided into two types: mucosal MCs and connective tissue MCs. Tryptase-expressing MCs (MCTs), tryptase and chymase-expressing MCs, and chymase-expressing MCs are classified based on their protease content. In terms of their roles in the disease, MCs are further categorized as inflammatory MCs, tumor-promoting MCs, and anti-tumor MCs [72, 73].
The number of MCs in tumor tissues is markedly lower than in peritumoral tissues in HCC [73,74,75]. The role of MCs in HCC is still debatable. On the one hand, MCs were demonstrated to promote the infiltration of MDSCs, which secreted IL-17, IL-17 then recruited Tregs, which produced IL-9; and IL-9, in turn, enhanced the immunosuppressive effect of MCs in HCC. There was a closed interaction loop among the three cell types that promoted tumor progression [76]. MCTs, the primary IL-17 producers, were reported to promote HCC angiogenesis [77, 78]. On the other hand, reduced intratumoral MCs in HCC were found to be related to a larger tumor size and a higher recurrence rate after liver transplantation, and by introducing microRNAs into tumor cells to inhibit the ERK1/2 signaling pathway, MCs could prevent HCC metastasis, showing the anti-tumor properties of MCs [75, 79]. MCs play different roles in HCC, possibly because different MC types have different functions, and researchers have not consistently classified or stratified MCs in depth. MCs and their products might also play different roles based on the different biological characteristics of various tumor cells. The granules and histamine produced by MCs could inhibit huh-6 cell growth and activate huh-6 cell apoptosis while enhancing HA22T/VGH cell proliferation [80]. Besides, higher peritumoral MC density was verified to be associated with a worse prognosis and an earlier recurrence of HCC [81].
Innate lymphoid cells
NK cells
The liver is the organ with the largest number of NK cells in the human body [82]. Unlike other lymphocytes, NK cells promote cellular activation and target cells for clearance using the absence of self. NK cell function is under the dual control of activating and inhibitory receptors. The interaction of inhibitory receptors and the major histocompatibility complex (MHC)-I on normal hepatocytes inhibits the activation of NK cells. A common mechanism of NK cell activation is the MHC-I downregulation of malignant cells. Target killing of NK cells is executed by perforin, granzyme, and apoptosis-inducing ligands [83].
The number of NK cells in HCC tissues is decreased, and their functions are impaired, which is related to the unfavorable prognosis for HCC [84]. An elevated level of HCC cell-derived exosomal circular ubiquitin-like with PHD and ring finger domain 1 RNA (circUHRF1) in the peripheral blood of HCC patients correlates with the reduced tumor infiltration of NK cells. CircUHRF1 can also suppress NK cell cytotoxicity by increasing TIM-3 expression, which is mediated by the degradation of miR-449c-5p [85]. Similarly, high levels of plasma TGF-β in patients with HCC lead to metabolic and functional defects in circulating NK cells [86]. Furthermore, transmembrane 4 L six family member 5 (TM4SF5), which is abundant in HCC, inhibits the expression of NK cytotoxicity-stimulated membrane ligands SLAMF6, SLAMF7, and MICA/B on target HCC cells, resulting in the decreased number and functional impairment of NK cells [87]. Moreover, the epithelial cell adhesion molecule (EpCAM) is a CSC biomarker in HCC [88, 89]. CSCs with high EpCAM expression in HCC can resist NK cell killing by promoting the carcinoembryonic antigen-related cell adhesion molecule 1 expression [90]. Notably, there is also complex cross talk among various immune cells in the TIME. MDSCs and tumor-associated macrophages (TAMs) in HCC can suppress NK cell cytotoxicity through NKp30 on NK cells [91], and Tregs can impair the immune responses of NK cells by releasing immunosuppressive cytokines IL-8, IL-10, and TGF-β [92].
NKT cells
NKT cells, expressing both T cell receptor (TCR)-chains and NK cell markers (NKp46 and NK1.1), can recognize lipids and glycolipids with the presentation of CD1d [93, 94]. NKT cells are categorized into type I and type II cells based on their TCR rearrangement and glycolipid reactivity [95]. Activated type I NKT cells, which is also called invariant NKT (iNKT) cells, can affect downstream immune responses by secreting interferon (IFN)-γ and IL-4 [96, 97]. Type II NKT cells have more Vα rearrangement sequences, and they can promote tumor growth and metastasis with the activation of sulfatides [98, 99].
In HCC, the number of iNKT cells in the tumor tissues is obviously lower compared with the adjacent non-tumor tissues, and their low infiltration in tumors is associated with the advanced stages and vascular invasion [100]. HCC is closely linked to liver inflammation, and iNKT cells can mediate anti-tumor effects by suppressing the inflammatory response in the process of β-catenin-induced liver tumorigenesis [101]. A synthetic glycolipid called α-galactosylceramide (α-GalCer) can inhibit the growth of hepatoma cells in the murine liver by stimulating NKT cells, which in turn activate NK cells [102]. The adoptive transfer of a small number of NKT cells that have been ex vivo treated with HCC-derived antigens can suppress the tumor growth in HCC mice, and the effect is correlated with NKT cell number, STAT4 expression, and serum levels of IL-12, IFN-γ, and IL-4 [103]. Furthermore, DCs pulsed with tumor antigens have been shown to inhibit HCC progression by activating NKT and CD8 + lymphocytes and increasing IFN-γ production [104]. NKT cells can be recruited to the liver via CXCR6-CXCL16 in the murine HCC models. CXCR6-deficient mice have an apparent higher tumor burden and tumor progression after intraperitoneal injection of DEN due to a reduction of iNKT and CD4 + T cells in the liver [105, 106]. Bile acid metabolism usually has a certain impact on the immune system of the body. Primary bile acids can promote the recruitment of NKT cells to the liver by upregulating the expression of CXCL16, thereby inhibiting HCC progression, and secondary bile acids, which are converted from primary bile acids by relevant bacteria, play the opposite role [106, 107]. There are also subpopulations of NKT cells that are involved in HCC promotion. CD4 + iNKT cells, unlike their CD4- counterparts, can boost tumor growth by inhibiting the cytotoxicity of CD8 + T cells and promoting Th2 cytokine production in HCC [108, 109].
Gamma delta T cells
Gamma delta (γδ) T cells are the important fighters of the immune system, accounting for an average of 3.7% of CD3 + T cells in peripheral blood. Based on the TCR rearrangement, γδ T cells, the nonconventional T lymphocytes, can be divided into three groups: Vδ1, Vδ2, and Vδ3 T cells. Vδ2 T cells predominate in the blood, while the other two groups are abundant in tissues. They have a range of biological functions, including pathogen clearance, inflammation regulation, and tumor immunity [110, 111].
The infiltration of γδ T cells in HCC is significantly decreased compared with the peritumoral tissues, which may be due to their G2/M cell arrest and active apoptotic state in tumors, and the low infiltration was confirmed to be correlated with the poor prognosis of HCC [112, 113]. γδ T cells can secrete IFN-γ in the early stage, which is essential for anti-tumor immunity [114]. An in vitro study observed that γδ T cells could inhibit the viability of HCC cells, and histone deacetylase inhibitors and zoledronic acid could enhance the suppression [115]. In addition to the reduced number, the function of γδ T cells is also abnormal in HCC. The cytotoxicity of γδ T cells is suppressed by various factors. Tregs, as well as the imbalance between HSCs and γδ T cells, can impair the function of γδ T cells, [116, 117]. Furthermore, increased glutamine metabolism and decreased glucose and lipid metabolism in γδ T cells further exacerbate the cellular dysfunction [112]. Several studies have been conducted to improve the anti-tumor function of γδ T cells in HCC. Aminobisphosphonate has been shown to promote the expansion of peripheral Vδ2 T cells and inhibit tumor growth, providing a new approach for HCC therapy [118]. Vδ1 T cells engineered with soluble IL-15 and a glypican 3 (GPC-3)-receptor can efficiently destroy HCC cells [119]. Moreover, the cytotoxicity of γδ T cells in HCC can be restored after supplementation with normal Vδ2 T [112, 120].
Other innate immune cells
Mucosal-associated invariant T (MAIT) cells, mostly located at mucosal sites and the liver, are innate-like cells. MAIT cells can recognize the antigens presented by MHC-I-related protein 1. When activated, they can perform anti-cancer activity by producing cytotoxic cytokines and substances [121]. In HCC, MAIT cells are greatly reduced in tumors compared to adjacent tissues, which may be attributed to the downregulation of CCR6, CXCR6, and CCR9 on tumor-educated MAIT cells [122,123,124]. In addition, MAIT cells exhibit pro-tumor properties, accompanied by immune checkpoint upregulation, decreased secretion of IFN-γ and IL-17, and increased IL-8 production [122, 123]. Co-administration of 5-OP-RU (5-(2-oxopropylideneamino)-6D-ribitylaminouracil, microbial riboflavin-derived antigen) and CpG (Toll-like receptor 9 agonist) can suppress the HCC progression by activating MAIT cells to release IFN-γ and cytotoxic substances, together with the accumulation of CD8 + T cells and NK cells in vivo [124].
Helper-like innate lymphoid cells (ILCs) consist of three subgroups: ILC1s, ILC2s, and ILC3s, which are functionally equivalent to Th1, Th2, and Th17 cells, respectively, and play a vital role in cancers [125, 126]. Hepatic ILC1s, including embryonic and postnatal subsets, most closely resemble NK cells in phenotype and function [127, 128], and they have been shown to play a suppressor role in the liver metastasis of tumors. ILC1s can suppress liver metastasis by limiting metastatic seeding and producing effector molecules, and their cytotoxicity can be calibrated by the activating receptor NKp46 on ILC1s [129,130,131]. ILC2s are the most clearly defined subset of helper-like ILCs, and Bcl11b and TGF-β are required for their development [132, 133]. In HCC, ILC2s are enriched in tumor tissues and are related to a poor prognosis. ILC2s can promote HCC progression through the CXCL2-neutrophil and IL-13-B cell signaling pathways [134, 135]. ILC3s express RORgt, which is essential for their function [136]. In an in vitro study, ILC3s exerted cytotoxicity against HCC cells mediated by TRAIL [137]. However, in a murine HCC model, ILC3s lacking the natural cytotoxicity-triggering receptor (NCR − ILC3s) promoted HCC progression by orchestrating the IL-23/IL-17 axis [138]. Similarly, a decreased serum short-chain fatty acid (SCFA) level due to the loss of the gut microbiota Lactobacillus reuteri in HCC mice promoted the release of IL-17A by ILC3s in tumors, which boosted tumor growth [139]. The contradictory conclusions of the in vivo and in vitro studies may be attributed to the remodeling of ILC3s by the TME, and further investigation is needed [140].
Adaptive immune cells in HCC
T and B cells, the adaptive immune cells, are essential for HCC immunity. Their functions and immunotherapy applications in HCC have received a lot of interest [5]. Here, we provide a summary of recent developments.
Conventional T cells consist of CD8 + and CD4 + T cells, and the former outnumber the latter in the liver; CD8 + T cells are the main tumor-infiltrating lymphocytes that perform anti-tumor functions [141, 142]. CD4 + T cells, mainly including CD4 + T-helper (Th) cells and Tregs, are also crucial in tumor immunity [143]. In HCC, CD4 + effector memory T (Tem) cells and Tregs progressively grow in number from the adjacent non-tumor region to the leading-edge area (slightly) to the tumor core (significantly), whereas CD8 + Tem cells showed the opposite trend [144]. The inhibition of CD8 + T cell infiltration by TAMs and plasma cells may be one reason for the reduction of CD8 + T cells in HCC [145, 146]. CD8 + T cells also exhibit an exhausted state in HCC with a high expression of PD-1 and LAG-3, which is a gradual and ongoing process that peaks in TNM stage II tumors [147, 148]. Multiple factors contribute to the exhaustion of CD8 + T cells. Firstly, tumor endothelial cells, MDSC-like macrophages, M2 macrophages, and CAFs in HCC may facilitate the formation of CD8 + T cell exhaustion [149,150,151,152]. Secondly, TGF-β1 derived from HCC cells can upregulate PD-1 and CTLA-4 expression on T lymphocytes via the CaN/NFATc1 pathway and accelerate T cell apoptosis [153]. Thirdly, abnormal glycolytic flux and lactate synthesis, as well as alterations in S-adenosylmethionine metabolism, can promote the development of exhausted T cells [154, 155]. Tregs are immunosuppressive cells, and exosomal circRNAs and IL-10 produced by HCC cells can promote the stability and expansion of them via various signaling pathways [156, 157]. HBV infection is the leading cause of more than half of HCC cases worldwide, and the hepatitis B-induced IL-8 can drive preferential Treg polarization mediated by liver sinusoidal endothelial cell-derived TGF-β [158,159,160]. Furthermore, lactic acid can stimulate PD-1 expression on Tregs in HCC, leading to the enhanced immunosuppressive properties of Tregs [161]. It is noteworthy that Tregs recruited by circulating tumor cells (CTCs)-derived CCL5 in HCC can promote CTC metastatic seeding, which may contribute to the development of novel anti-metastasis treatment for HCC [162].
B cells are a type of antigen-presenting cell that can present antigens to T cells and produce specific antibodies. Plasma cells, which originate from B cells, are involved in antibody production. The function of B cells in HCC remains controversial [163]. Some studies showed that the proportion of CD19 + B cells was higher in HCC tissues than in paracancerous tissues, and an increased B cell number in tumors was not only associated with an advanced tumor stage but also promoted immune escape in HCC [146],[164]. Additionally, B cells in HCC tissues have somatic hypermutations and class-switched recombinations of the IgG phenotype that are not seen in normal liver tissues [165]. Since there is little direct communication between HCC cells and B cells, B cells may modulate tumor immunity through other mechanisms [145]. Regulating B cells (Bregs), originally defined as CD19 + CD24hiCD38hi cells, play an immunosuppressive role in tumors, and the number of Bregs expressing IL-10 increases in HCC. Exosomal high-mobility group box 1 produced by HCC cells can promote Breg expansion via the TLR-MAPK signaling pathway, and TLR activation can also increase the expression of Bcl-6, which is required for HCC environmental factors to promote the formation of PD-1high Bregs [146], [163, 166,167,168]. In addition, CXCR3 + B cells, which account for approximately 45% of infiltrating B cells in HCC, can induce M2b macrophage polarization via IgG pathways, and CCR6 + B cells can promote angiogenesis by interacting with CCL20 generated by HCC cells [169, 170]. However, Zhang and colleagues discovered that HCC exhibited a global alteration in the B cell compartments with a decrease in CD20 + B cells and all B cell subsets, and that high levels of CD20 + B cells, IgM + B cells, CD27 − B cells, naive B cells, and plasma cells in HCC were associated with improved clinical outcomes [171]. Different criteria for defining B cells and their subgroups may be the cause of the contradictory results, and more research is required in the future.
HCC immunotherapies
As HCC is an inflammation-related cancer, immunotherapy is a promising treatment option [172]. As a result of in-depth research into the TIME of HCC, new immunotherapy methods are constantly emerging. We summarize the most recent representative data from preclinical and clinical trials of immunotherapeutic strategies (shown in Fig. 2, Tables 12) for HCC and discuss their clinical application prospects.
Immune checkpoint inhibitor therapy
Immune checkpoints are specific membrane molecules that are related to immune escape in cancers. There are many studies on the major immune checkpoints, such as CTLA-4, PD-1, and PD-L1, for immunotherapy [173]. Tremelimumab is a CTLA-4 blockade. A preliminary clinical study found that HCC patients treated with tremelimumab had a median overall survival (OS) of 8.2 months and a disease control rate of 76.4% [174]. The results of the KEYNOTE-240 trial showed that the median OS and progression-free survival (PFS) with pembrolizumab were 13.9 months and 3.0 months, respectively, when it was studied as a second-line therapy [175]. Additionally, pembrolizumab had a 10% overall response rate in HCC patients who failed sorafenib treatment in a recent study [176]. What is more, the median OS with single-agent nivolumab as first-line therapy for HCC was 16.4 months in the CheckMate-459 trial [177]. Although these single ICI therapies have certain anti-tumor effects in HCC patients, the efficacy is still unsatisfactory, which may be associated with the complex TIME of HCC.
As multiple mechanisms are involved in the tumorigenesis and progression of HCC, combining ICIs with other drugs or treatments may be a promising approach for HCC treatment. First, the combination of two ICIs targeting different immune checkpoints is effective for HCC therapy [178, 179]. The objective response rate (ORR) of tremelimumab combined with durvalumab (an anti-PD-L1 monoclonal antibody) in HCC patients was 24.0% in a clinical trial [178]. Likewise, another study found that nivolumab plus ipilimumab (an anti-CTLA-4 agent) showed a long-lasting response and a promising response rate in HCC patients who had received sorafenib treatment before [179]. Second, ICIs combined with anti-angiogenic drugs are effective against HCC [180,181,182]. VEGF overexpression in HCC is linked to a high density of tumor blood vessels [183]. In the IMbrave-150 trial, patients with atezolizumab (a PD-L1 inhibitor) plus bevacizumab (a VEGF blockade) had an ORR of 30% and a median OS of 19.2 months, and the combination therapy also exhibited good efficacy for HCC patients in South Korea in the real world [180, 181]. Furthermore, camrelizumab (an anti-PD-1 drug) in combination with apatinib (a VEGFR2 monoclonal antibody) demonstrated favorable perioperative outcomes in patients with surgically resectable HCC [182]. Third, ICIs combined with TKIs such as lenvatinib and cabozantinib are an effective treatment option [184, 185]. In a phase Ib study, the combination treatment of pembrolizumab and lenvatinib had an ORR of 46.0% and a median OS of 22 months in HCC patients [184]. Moreover, neoadjuvant therapy of nivolumab combined with cabozantinib could convert locally advanced HCC to resectable disease with the promotion of anti-tumor immunity [185]. At last, ICIs in combination with locoregional treatments, such as ablation, TACE, and stereotactic body radiotherapy, are available for HCC treatment [186,187,188].
Adoptive cell therapy
There are two cell types of adoptive cell therapy (ACT) that are applied in the preclinical and clinical studies of HCC: genetically modified lymphocytes and cytokine-induced killer cells (CIKs). The objective of genetic modification of lymphocytes is to equip them with chimeric antigen receptor (CAR) to better target tumor-specific antigens [189]. GPC-3, a carcinoembryonic proteoglycan on the tumor cell membrane, and CD133, an endothelial progenitor cell marker, are two popular immunotherapy targets in recent HCC research [190, 191]. GPC-3-targeted CAR-T cells have been proven to have good safety and efficacy in the therapy of HCC, and GPC-3-CAR-T cells with the co-expression of IL-15 and IL-21 demonstrated superior cell proliferation and anti-tumor ability [192,193,194]. 8F8 is a low-affinity, GPC-3 specific antibody. 8F8-targeted CAR-T cells can withstand exhaustion and maintain anti-tumor effects in tumor lesions for a long time [195]. Similarly, CD133-targeted CAR-T cells show significant cytotoxicity against HCC cells [191]. What is more, GPC-3-targeted CAR-NK cells/Vδ1 T cells also exhibit robust anti-tumor activity in HCC [119, 196].
CIKs, exhibiting the phenotype and cytotoxicity of T cells and NK cells, contain multiple cell subsets [197]. CIKs can identify and destroy HCC CSCs through NKG2d-ligand recognition, thereby inhibiting HCC progression [198]. There is a cross talk between CIKs and MDSCs in HCC, and suppressing MDSCs can enhance the cytotoxicity of CIKs [199]. Adjuvant immunotherapy with CIKs in HCC patients could improve prognosis and quality of life when combined with radical therapy, TACE, or radiofrequency ablation [200,201,202], and receiving CIK therapy after curative treatment was proved to be cost-effective due to the reduced recurrence and prolonged survival of HCC [203]. In addition, PD-L1 and PD-1 might be used as two biomarkers to guide CIK treatment in HCC because high PD-L1 expression and a high infiltration of PD-1 + lymphocytes in HCC were all found to be correlated with good efficacy for CIK therapy [204, 205].
Cytokine therapy
In terms of cytokine therapy, IFN-α has received more attention and is still being studied. IFN-α is a type I IFN with immunostimulatory and anti-vascular properties. Recombinant IFN-α is the first immunotherapy for human cancers [206]. According to some studies, IFN-α administration did not significantly improve the survival of HCC patients, and adjuvant IFN-α therapy after resection had no effect on RFS in HCC patients [207, 208]. Some studies, however, found that IFN-α could provide a significant benefit in both OS and RFS for HCC patients undergoing curative surgery, and that IFN-α therapeutic response could be predicted by hepatic retinoic acid-inducible gene-I and tetratricopeptide repeats 3 [209,210,211]. As a result of the heterogeneity of treatment responses, INF-α is not widely used in the clinical practice of HCC therapy.
Recent studies have confirmed that IFN-α treatment can recruit the cytotoxic T cells in murine HCC models by remodeling glucose metabolism, as well as promote the infiltration of cytotoxic CD169 + macrophages and M1-like macrophages, and that combined treatment with ICIs or sorafenib has synergistic anti-tumor efficacy [212,213,214]. These findings open a new avenue for the future use of IFN-α in the HCC therapy.
Therapeutic vaccines
The main purpose of using cancer vaccines is to generate specific anti-tumor responses with strong potency. Classic cancer vaccines include peptide vaccines and antigen-pulsed DC vaccines. Tumor-associated antigens (TAAs), such as AFP, GPC-3, and telomerase, are common targets for HCC-specific peptide vaccines [215]. Recent research has primarily concentrated on GPC-3-related HCC vaccines. Because of the elevated density of peptide-specific cytotoxic T lymphocytes (CTLs) in the TME, HCC patients with high GPC-3 expression in tumor tissues and/or high content of GPC-3 in plasma have a high response rate and a good prognosis for the GPC-3 vaccine [216]. H8B-BsAb, a novel tetravalent bispecific anti-GPC-3 antibody, showed significant anti-tumor effect in a xenograft mouse model of HCC, and may be a potential candidate for HCC therapy [217]. Aside from antibodies, the GPC-3-modified molecules perform well against HCC [218,219,220]. Besides, other peptide vaccines, such as the aspartate-hydroxylase vaccine, the HA (the fusion of high-mobility group nucleosome binding protein 1 and AFP) vaccine, and the VEGF vaccine, also have promising applications in the treatment of HCC [221,222,223].
DC vaccines have been widely used in the treatment of various cancers, including HCC [224, 225]. A meta-analysis found that DC vaccines had a higher ORR and longer median OS and PFS compared to peptide vaccines in HCC treatment [226]. Many studies on novel DC vaccines have recently emerged, laying a solid theoretical foundation for the development of effective DC vaccines in the treatment of HCC. CD40L on activated CD4 + Th cells can communicate with CD40 on DCs to promote the secretion of Th1 cytokines by DCs, and the CD40L-DCs were confirmed to improve the anti-tumor activity of the AFP-DC vaccine in an orthotopic HCC mouse model, and the combination of them could significantly suppress tumor progression, accompanied by a robust Th1-shift in the TME and increased tumor cell apoptosis [227]. Furthermore, CSC/DC fusion cells could promote CTL accumulation in HCC and enhance anti-tumor immunity in animal experiments [228]. Recently, a DC-based nano-vaccine that consisted of silicon phthalocyanine dichloride, Fe(III)-captopril, and the exfoliated membrane of mature DCs stimulated by specific H22 cell neoantigens appeared, and it was proved to induce the activation and proliferation of neoantigen-specific T cells, as well as convert N2-type neutrophils to N1-type neutrophils in H22 tumors [229]. In addition, the combination of DC vaccines with other treatments such as ICIs, CIKs, and ACT demonstrates robust anti-tumor efficacy and may be a promising treatment strategy for HCC [230,231,232,233].
Oncolytic virus therapy
Oncolytic viruses (OVs) can spread through tumor tissues, replicate selectively in cancer cells, and annihilate them without impairing normal cells [234]. The most common OVs for HCC therapy in preclinical and clinical studies are vesicular stomatitis virus and adenovirus. Pexastigmogene devacirepvec (Pexa-Vec) is a main OV that is currently being investigated in HCC; however, the efficacy of Pexa-Vec in clinical trials is disappointing [235, 236]. Nonetheless, studies involving other OVs are ongoing and have yielded promising results in animal models of HCC.
The influenza virus (IV), an RNA virus, has been identified as a potentially effective oncolytic agent. In HCC mouse models, recombinant IV with PD-1 antibody or CTLA4-specific scFv could activate anti-tumor immunity [237, 238]. Vaccinia virus, which is a double-stranded DNA virus, could enhance anti-HCC effects when carried with IL-24 or Aphrocallistes vastus lectin [239, 240]. T cell immunoglobulin and ITIM domain (TIGIT) expressed on activated NK and T cells is a key checkpoint molecule. The poliovirus receptor (PVR) is the cognate ligand of TIGIT [241]. In a recent study, an adenovirus expressing a PD1-PVR fusion protein could inhibit tumor growth mediated with CD8 + T cells in a mouse model of H22 ascites HCC, and it showed a better effect when combined with fludarabine [242]. However, OVs also have some drawbacks for application, mainly including non-specific distribution to organs and the generation of neutralizing antibodies [243, 244]. To overcome these shortcomings and improve the therapeutic efficacy of OVs, a research team exploited a polygalactosyl-b-agmatyl copolymer-coated oncolytic adenovirus, which displayed enhanced infectivity and tumor cell killing activity in vitro and provided a theoretical basis for the effective treatment of HCC with OVs in the future [245].
Conclusions
As indicated by immunological classification, HCC consists of a heterogeneous group of cancers with distinct etiologies and immune microenvironments. There are multilayered interwoven webs among various immune cell types in HCC, and different stages of HCC are often accompanied by phenotypic changes of different immune cells in the TME, requiring thoughtful treatment design to ensure the success of immunotherapy. Emerging preclinical and clinical evidence demonstrates the promising prospect of immunotherapeutic approaches for HCC. With the advent of cutting-edge technologies such as single-cell approaches and multiplex histological analysis that preserve spatial information, it is possible to gain a better understanding of HCC immune status and discover new immunotherapy targets and patient-tailored approaches.
Data availability
The corresponding author will respond to reasonable requests for the datasets used in the current work.
References
Aizarani N, Saviano A, Sagar, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019;572(7768):199–204. https://doi.org/10.1038/s41586-019-1373-2.
MacParland SA, Liu JC, Ma XZ, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018;9(1):4383. https://doi.org/10.1038/s41467-018-06318-7.
Kubes P, Jenne C. Immune responses in the liver. Annu Rev Immunol. 2018;36:247–77. https://doi.org/10.1146/annurev-immunol-051116-052415.
Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hepatol Int. 2019;13(2):125–37. https://doi.org/10.1007/s12072-018-9919-1.
Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151–72. https://doi.org/10.1038/s41571-021-00573-2.
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502. https://doi.org/10.1016/S0140-6736(17)31046-2.
Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52. https://doi.org/10.1016/S1470-2045(18)30351-6.
Leslie J, Mackey JBG, Jamieson T, et al. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut. 2022;71(10):2093–106. https://doi.org/10.1136/gutjnl-2021-326259.
Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol. 2021;18(1):112–27. https://doi.org/10.1038/s41423-020-00572-w.
Woo J, Lu L, Rao AS, et al. Isolation, phenotype, and allostimulatory activity of mouse liver dendritic cells. Transplantation. 1994;58(4):484–91. https://doi.org/10.1097/00007890-199408270-00015.
Yrlid U, Cerovic V, Milling S, et al. Plasmacytoid dendritic cells do not migrate in intestinal or hepatic lymph. J Immunol. 2006;177(9):6115–21. https://doi.org/10.4049/jimmunol.177.9.6115.
Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations. Int Rev Cell Mol Biol. 2019;348:1–68. https://doi.org/10.1016/bs.ircmb.2019.07.004.
Zhang Q, He Y, Luo N, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell. 2019;179(4):829-845.e20. https://doi.org/10.1016/j.cell.2019.10.003.
Sun Y, Wu L, Zhong Y, et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell. 2021;184(2):404-421.e16. https://doi.org/10.1016/j.cell.2020.11.041.
Pang L, Ng KT, Liu J, et al. Plasmacytoid dendritic cells recruited by HIF-1α/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma. Cancer Lett. 2021;522:80–92. https://doi.org/10.1016/j.canlet.2021.09.022.
Suthen S, Lim CJ, Nguyen PHD, et al. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology. 2022;76(5):1329–44. https://doi.org/10.1002/hep.32419.
Santos PM, Menk AV, Shi J, Tsung A, Delgoffe GM, Butterfield LH. Tumor-derived α-fetoprotein suppresses fatty acid metabolism and oxidative phosphorylation in dendritic cells. Cancer Immunol Res. 2019;7(6):1001–12. https://doi.org/10.1158/2326-6066.CIR-18-0513.
Um SH, Mulhall C, Alisa A, et al. Alpha-fetoprotein impairs APC function and induces their apoptosis. J Immunol. 2004;173(3):1772–8. https://doi.org/10.4049/jimmunol.173.3.1772.
Yamamoto M, Tatsumi T, Miyagi T, et al. α-Fetoprotein impairs activation of natural killer cells by inhibiting the function of dendritic cells. Clin Exp Immunol. 2011;165(2):211–9. https://doi.org/10.1111/j.1365-2249.2011.04421.x.
Li L, Li SP, Min J, Zheng L. Hepatoma cells inhibit the differentiation and maturation of dendritic cells and increase the production of regulatory T cells. Immunol Lett. 2007;114(1):38–45. https://doi.org/10.1016/j.imlet.2007.09.003.
Xiong S, Dong L, Cheng L. Neutrophils in cancer carcinogenesis and metastasis. J Hematol Oncol. 2021;14(1):173. https://doi.org/10.1186/s13045-021-01187-y.
Kuang DM, Zhao Q, Wu Y, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54(5):948–55. https://doi.org/10.1016/j.jhep.2010.08.041.
Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16(3):183–94. https://doi.org/10.1016/j.ccr.2009.06.017.
Sagiv JY, Michaeli J, Assi S, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015;10(4):562–73. https://doi.org/10.1016/j.celrep.2014.12.039.
Peng ZP, Jiang ZZ, Guo HF, et al. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol. 2020;73(4):906–17. https://doi.org/10.1016/j.jhep.2020.05.004.
Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology. 2016;150(7):1646-1658.e17. https://doi.org/10.1053/j.gastro.2016.02.040.
Cristinziano L, Modestino L, Antonelli A, et al. Neutrophil extracellular traps in cancer. Semin Cancer Biol. 2022;79:91–104. https://doi.org/10.1016/j.semcancer.2021.07.011.
Yang LY, Luo Q, Lu L, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020;13(1):3. https://doi.org/10.1186/s13045-019-0836-0.
Yan C, Yang Q, Gong Z. Tumor-associated neutrophils and macrophages promote gender disparity in hepatocellular carcinoma in zebrafish. Cancer Res. 2017;77(6):1395–407. https://doi.org/10.1158/0008-5472.CAN-16-2200.
Shigesawa T, Maehara O, Suda G, et al. Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling. Carcinogenesis. 2021;42(1):58–69. https://doi.org/10.1093/carcin/bgaa049.
Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma—from origin to clinical implications. Nat Rev Gastroenterol Hepatol. 2022;19(1):26–44. https://doi.org/10.1038/s41575-021-00508-3.
Zhou SL, Yin D, Hu ZQ, et al. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology. 2019;70(4):1214–30. https://doi.org/10.1002/hep.30630.
Esteban-Fabró R, Willoughby CE, Piqué-Gili M, et al. Cabozantinib enhances anti-PD1 activity and elicits a neutrophil-based immune response in hepatocellular carcinoma. Clin Cancer Res. 2022;28(11):2449–60. https://doi.org/10.1158/1078-0432.CCR-21-2517.
Ikeda M, Morimoto M, Tajimi M, et al. A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Invest New Drugs. 2019;37(1):118–26. https://doi.org/10.1007/s10637-018-0636-3.
Sarker D, Plummer R, Meyer T, et al. MTL-CEBPA, a Small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label. Phase I Trial Clin Cancer Res. 2020;26(15):3936–46. https://doi.org/10.1158/1078-0432.CCR-20-0414.
Fan Y, Li S, Ding X, et al. First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers. BMC Cancer. 2019;19(1):279. https://doi.org/10.1186/s12885-019-5471-1.
Blériot C, Barreby E, Dunsmore G, et al. A subset of Kupffer cells regulates metabolism through the expression of CD36. Immunity. 2021;54(9):2101-2116.e6. https://doi.org/10.1016/j.immuni.2021.08.006.
Liu N, Wang X, Steer CJ, Song G. MicroRNA-206 promotes the recruitment of CD8+ T cells by driving M1 polarisation of Kupffer cells. Gut. 2022;71(8):1642–55. https://doi.org/10.1136/gutjnl-2021-324170.
Ramavath NN, Gadipudi LL, Provera A, et al. Inducible T-cell costimulator mediates lymphocyte/macrophage interactions during liver repair. Front Immunol. 2021;12:786680. https://doi.org/10.3389/fimmu.2021.786680.
Lacotte S, Slits F, Orci LA, et al. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. Oncoimmunology. 2016;5(11):e1234565. https://doi.org/10.1080/2162402X.2016.1234565.
Sheng J, Zhang J, Wang L, et al. Topological analysis of hepatocellular carcinoma tumour microenvironment based on imaging mass cytometry reveals cellular neighbourhood regulated reversely by macrophages with different ontogeny. Gut. 2022;71(6):1176–91. https://doi.org/10.1136/gutjnl-2021-324339.
Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7–H1/programmed death-1 interactions. Cancer Res. 2009;69(20):8067–75. https://doi.org/10.1158/0008-5472.CAN-09-0901.
Li H, Wu K, Tao K, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012;56(4):1342–51. https://doi.org/10.1002/hep.25777.
Huan HB, Wen XD, Chen XJ, et al. Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells. Brain Behav Immun. 2017;59:118–34. https://doi.org/10.1016/j.bbi.2016.08.016.
Sun K, Xu L, Jing Y, et al. Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. Cancer Lett. 2017;388:198–207. https://doi.org/10.1016/j.canlet.2016.12.004.
Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res. 2012;72(16):3977–86. https://doi.org/10.1158/0008-5472.CAN-12-0938.
Wang Y, Zhang T, Sun M, et al. Therapeutic values of myeloid-derived suppressor cells in hepatocellular carcinoma: facts and hopes. Cancers (Basel). 2021;13(20):5127. https://doi.org/10.3390/cancers13205127.
Liu X, Zhao S, Sui H, et al. MicroRNAs/LncRNAs modulate MDSCs in tumor microenvironment. Front Oncol. 2022;12:772351. https://doi.org/10.3389/fonc.2022.772351.
Haist M, Stege H, Grabbe S, Bros M. The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment. Cancers (Basel). 2021;13(2):210. https://doi.org/10.3390/cancers13020210.
Gao XH, Tian L, Wu J, et al. Circulating CD14+ HLA-DR-/low myeloid-derived suppressor cells predicted early recurrence of hepatocellular carcinoma after surgery. Hepatol Res. 2017;47(10):1061–71. https://doi.org/10.1111/hepr.12831.
Elwan N, Salem ML, Kobtan A, et al. High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients. Immunol Invest. 2018;47(2):169–80. https://doi.org/10.1080/08820139.2017.1407787.
Lee WC, Wang YC, Cheng CH, et al. Myeloid-derived suppressor cells in the patients with liver resection for hepatitis B virus-related hepatocellular carcinoma. Sci Rep. 2019;9(1):2269. https://doi.org/10.1038/s41598-019-38785-3.
Li T, Zhang X, Lv Z, Gao L, Yan H. Increased expression of myeloid-derived suppressor cells in patients with HBV-related hepatocellular carcinoma. Biomed Res Int. 2020;2020:6527192. https://doi.org/10.1155/2020/6527192.
Tomiyama T, Itoh S, Iseda N, et al. Myeloid-derived suppressor cell infiltration is associated with a poor prognosis in patients with hepatocellular carcinoma. Oncol Lett. 2022;23(3):93. https://doi.org/10.3892/ol.2022.13213.
Zhou Z, Lai P, Zhang S, et al. The relationship between hepatic myeloid-derived suppressor cells and clinicopathological parameters in patients with chronic liver disease. Biomed Res Int. 2021;2021:6612477. https://doi.org/10.1155/2021/6612477.
Li BH, Jiang W, Zhang S, et al. The spleen contributes to the increase in PMN-MDSCs in orthotopic H22 hepatoma mice. Mol Immunol. 2020;125:95–103. https://doi.org/10.1016/j.molimm.2020.07.002.
Fondevila MF, Fernandez U, Heras V, et al. Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis. J Hepatol. 2022;77(1):15–28. https://doi.org/10.1016/j.jhep.2022.02.003.
Xu Y, Fang F, Jiao H, et al. Activated hepatic stellate cells regulate MDSC migration through the SDF-1/CXCR4 axis in an orthotopic mouse model of hepatocellular carcinoma. Cancer Immunol Immunother. 2019;68(12):1959–69. https://doi.org/10.1007/s00262-019-02414-9.
Hsieh CC, Hung CH, Chiang M, Tsai YC, He JT. Hepatic stellate cells enhance liver cancer progression by inducing myeloid-derived suppressor cells through interleukin-6 signaling. Int J Mol Sci. 2019;20(20):5079. https://doi.org/10.3390/ijms20205079.
Xu Y, Huang Y, Xu W, et al. Activated hepatic stellate cells (HSCs) exert immunosuppressive effects in hepatocellular carcinoma by producing complement C3. Onco Targets Ther. 2020;13:1497–505. https://doi.org/10.2147/OTT.S234920.
Liu G, Sun J, Yang ZF, et al. Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis. Cell Death Dis. 2021;12(3):260. https://doi.org/10.1038/s41419-021-03545-7.
Deng Y, Cheng J, Fu B, et al. Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells. Oncogene. 2017;36(8):1090–101. https://doi.org/10.1038/onc.2016.273.
Li Q, Ni Y, Zhang L, et al. HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Signal Transduct Target Ther. 2021;6(1):76. https://doi.org/10.1038/s41392-020-00453-8.
Chiu DK, Tse AP, Xu IM, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun. 2017;8(1):517. https://doi.org/10.1038/s41467-017-00530-7.
Cao M, Huang W, Chen Y, et al. Chronic restraint stress promotes the mobilization and recruitment of myeloid-derived suppressor cells through β-adrenergic-activated CXCL5-CXCR2-Erk signaling cascades. Int J Cancer. 2021;149(2):460–72. https://doi.org/10.1002/ijc.33552.
Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol. 2011;46(2):156–64. https://doi.org/10.3109/00365521.2010.516450.
Deng X, Li X, Guo X, et al. Myeloid-derived suppressor cells promote tumor growth and sorafenib resistance by inducing FGF1 upregulation and fibrosis. Neoplasia. 2022;28:100788. https://doi.org/10.1016/j.neo.2022.100788.
Liu H, Ling CC, Yeung WHO, et al. Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling. Cell Death Dis. 2021;12(5):489. https://doi.org/10.1038/s41419-021-03788-4.
Wei J, Fang D. Endoplasmic reticulum stress signaling and the pathogenesis of hepatocarcinoma. Int J Mol Sci. 2021;22(4):1799. https://doi.org/10.3390/ijms22041799.
Zhou B, Lu D, Wang A, et al. Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma. Mol Ther Nucleic Acids. 2021;26:1051–65. https://doi.org/10.1016/j.omtn.2021.09.014.
Nan J, Xing YF, Hu B, et al. Endoplasmic reticulum stress induced LOX-1+ CD15+ polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma. Immunology. 2018;154(1):144–55. https://doi.org/10.1111/imm.12876.
Dahlin JS, Maurer M, Metcalfe DD, Pejler G, Sagi-Eisenberg R, Nilsson G. The ingenious mast cell: contemporary insights into mast cell behavior and function. Allergy. 2022;77(1):83–99. https://doi.org/10.1111/all.14881.
Cildir G, Yip KH, Pant H, Tergaonkar V, Lopez AF, Tumes DJ. Understanding mast cell heterogeneity at single cell resolution. Trends Immunol. 2021;42(6):523–35. https://doi.org/10.1016/j.it.2021.04.004.
Cervello M, Foderàa D, Florena AM, et al. Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: possible role in tumor promotion and angiogenesis. World J Gastroenterol. 2005;11(30):4638–43. https://doi.org/10.3748/wjg.v11.i30.4638.
Rohr-Udilova N, Tsuchiya K, Timelthaler G, et al. Morphometric analysis of mast cells in tumor predicts recurrence of hepatocellular carcinoma after liver transplantation. Hepatol Commun. 2021;5(11):1939–52. https://doi.org/10.1002/hep4.1770.
Yang Z, Zhang B, Li D, et al. Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One. 2010;5(1):e8922. https://doi.org/10.1371/journal.pone.0008922.
Grizzi F, Franceschini B, Chiriva-Internati M, Liu Y, Hermonat PL, Dioguardi N. Mast cells and human hepatocellular carcinoma. World J Gastroenterol. 2003;9(7):1469–73. https://doi.org/10.3748/wjg.v9.i7.1469.
Tu JF, Pan HY, Ying XH, Lou J, Ji JS, Zou H. Mast Cells comprise the major of interleukin 17-producing cells and predict a poor prognosis in hepatocellular carcinoma. Medicine (Baltimore). 2016;95(13):e3220. https://doi.org/10.1097/MD.0000000000003220.
Xiong L, Zhen S, Yu Q, Gong Z. HCV-E2 inhibits hepatocellular carcinoma metastasis by stimulating mast cells to secrete exosomal shuttle microRNAs. Oncol Lett. 2017;14(2):2141–6. https://doi.org/10.3892/ol.2017.6433.
Lampiasi N, Azzolina A, Montalto G, Cervello M. Histamine and spontaneously released mast cell granules affect the cell growth of human hepatocellular carcinoma cells. Exp Mol Med. 2007;39(3):284–94. https://doi.org/10.1038/emm.2007.32.
Ju MJ, Qiu SJ, Gao Q, et al. Combination of peritumoral mast cells and T-regulatory cells predicts prognosis of hepatocellular carcinoma. Cancer Sci. 2009;100(7):1267–74. https://doi.org/10.1111/j.1349-7006.2009.01182.x.
Zhang Y, Wu Y, Shen W, Wang B, Yuan X. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review). Mol Med Rep. 2022;25(6):208. https://doi.org/10.3892/mmr.2022.12724.
Zhang W, Zhao Z, Li F. Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy. Mol Immunol. 2022;144:58–70. https://doi.org/10.1016/j.molimm.2022.02.015.
Yu L, Liu X, Wang X, et al. Nomogram for prediction of long-term survival with hepatocellular carcinoma based on NK cell counts. Ann Hepatol. 2022;27(2):100672. https://doi.org/10.1016/j.aohep.2022.100672.
Zhang PF, Gao C, Huang XY, et al. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer. 2020;19(1):110. https://doi.org/10.1186/s12943-020-01222-5.
Zecca A, Barili V, Canetti D, et al. Energy metabolism and cell motility defect in NK-cells from patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2020;69(8):1589–603. https://doi.org/10.1007/s00262-020-02561-4.
Sun H, Kim E, Ryu J, et al. TM4SF5-mediated liver malignancy involves NK cell exhaustion-like phenotypes. Cell Mol Life Sci. 2021;79(1):49. https://doi.org/10.1007/s00018-021-04051-x.
Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest. 2013;123(5):1911–8. https://doi.org/10.1172/JCI66024.
Yoon SM, Gerasimidou D, Kuwahara R, et al. Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Hepatology. 2011;53(3):964–73. https://doi.org/10.1002/hep.24122.
Park DJ, Sung PS, Kim JH, et al. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer. 2020;8(1):e000301. https://doi.org/10.1136/jitc-2019-000301.
Hoechst B, Voigtlaender T, Ormandy L, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 2009;50(3):799–807. https://doi.org/10.1002/hep.23054.
Langhans B, Alwan AW, Krämer B, et al. Regulatory CD4+ T cells modulate the interaction between NK cells and hepatic stellate cells by acting on either cell type. J Hepatol. 2015;62(2):398–404. https://doi.org/10.1016/j.jhep.2014.08.038.
Bandyopadhyay K, Marrero I, Kumar V. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol. 2016;13(3):337–46. https://doi.org/10.1038/cmi.2015.115.
Nelson A, Lukacs JD, Johnston B. The current landscape of NKT cell immunotherapy and the hills ahead. Cancers (Basel). 2021;13(20):5174. https://doi.org/10.3390/cancers13205174.
Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol. 2004;4(3):231–7. https://doi.org/10.1038/nri1309.
Coquet JM, Chakravarti S, Kyparissoudis K, et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1-NKT cell population. Proc Natl Acad Sci USA. 2008;105(32):11287–92. https://doi.org/10.1073/pnas.0801631105.
Robertson FC, Berzofsky JA, Terabe M. NKT cell networks in the regulation of tumor immunity. Front Immunol. 2014;5:543. https://doi.org/10.3389/fimmu.2014.00543.
Macho-Fernandez E, Brigl M. The extended family of CD1d-restricted NKT cells: sifting through a mixed bag of TCRs, antigens, and functions. Front Immunol. 2015;6:362. https://doi.org/10.3389/fimmu.2015.00362.
Renukaradhya GJ, Khan MA, Vieira M, Du W, Gervay-Hague J, Brutkiewicz RR. Type I NKT cells protect (and type II NKT cells suppress) the host’s innate antitumor immune response to a B-cell lymphoma. Blood. 2008;111(12):5637–45. https://doi.org/10.1182/blood-2007-05-092866.
Xiao YS, Gao Q, Xu XN, et al. Combination of intratumoral invariant natural killer T cells and interferon-gamma is associated with prognosis of hepatocellular carcinoma after curative resection. PLoS One. 2013;8(8):e70345. https://doi.org/10.1371/journal.pone.0070345.
Anson M, Crain-Denoyelle AM, Baud V, et al. Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest. 2012;122(2):586–99. https://doi.org/10.1172/JCI43937.
Miyagi T, Takehara T, Tatsumi T, et al. CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver. Int J Cancer. 2003;106(1):81–9. https://doi.org/10.1002/ijc.11163.
Margalit M, Shibolet O, Klein A, et al. Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes. Int J Cancer. 2005;115(3):443–9. https://doi.org/10.1002/ijc.20889.
Shibolet O, Alper R, Zlotogarov L, et al. NKT and CD8 lymphocytes mediate suppression of hepatocellular carcinoma growth via tumor antigen-pulsed dendritic cells. Int J Cancer. 2003;106(2):236–43. https://doi.org/10.1002/ijc.11201.
Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391):eaan5931. https://doi.org/10.1126/science.aan5931.
Mossanen JC, Kohlhepp M, Wehr A, et al. CXCR6 inhibits hepatocarcinogenesis by promoting natural killer T- and CD4+ T-cell-dependent control of senescence. Gastroenterology. 2019;156(6):1877-1889.e4. https://doi.org/10.1053/j.gastro.2019.01.247.
Shi H, Ter Horst R, Nielen S, et al. The gut microbiome as mediator between diet and its impact on immune function. Sci Rep. 2022;12(1):5149. https://doi.org/10.1038/s41598-022-08544-y.
Bricard G, Cesson V, Devevre E, et al. Enrichment of human CD4+ V(alpha)24/Vbeta11 invariant NKT cells in intrahepatic malignant tumors. J Immunol. 2009;182(8):5140–51. https://doi.org/10.4049/jimmunol.0711086.
Crowe NY, Coquet JM, Berzins SP, et al. Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med. 2005;202(9):1279–88. https://doi.org/10.1084/jem.20050953.
Deng J, Yin H. Gamma delta (γδ) T cells in cancer immunotherapy; where it comes from, where it will go? Eur J Pharmacol. 2022;919:174803. https://doi.org/10.1016/j.ejphar.2022.174803.
Chen S, Lv T, Sun G, et al. Reciprocal alterations in circulating and hepatic gamma-delta T cells in patients with primary biliary cholangitis. Hepatol Int. 2022;16(1):195–206. https://doi.org/10.1007/s12072-021-10267-7.
He W, Hu Y, Chen D, et al. Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2+ γδ T cell can be a promising complement. Clin Transl Med. 2022;12(4):e800. https://doi.org/10.1002/ctm2.800.
Zhao N, Dang H, Ma L, et al. Intratumoral γδ T-Cell infiltrates, chemokine (C-C Motif) ligand 4/chemokine (C-C Motif) ligand 5 protein expression and survival in patients with hepatocellular carcinoma. Hepatology. 2021;73(3):1045–60. https://doi.org/10.1002/hep.31412.
Gao Y, Yang W, Pan M, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med. 2003;198(3):433–42. https://doi.org/10.1084/jem.20030584.
Hoh A, Dewerth A, Vogt F, et al. The activity of γδ T cells against paediatric liver tumour cells and spheroids in cell culture. Liver Int. 2013;33(1):127–36. https://doi.org/10.1111/liv.12011.
Yi Y, He HW, Wang JX, et al. The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner. J Hepatol. 2013;58(5):977–83. https://doi.org/10.1016/j.jhep.2012.12.015.
Zhou BY, Gong JH, Cai XY, et al. An imbalance between stellate cells and γδT cells contributes to hepatocellular carcinoma aggressiveness and recurrence. Hepatol Int. 2019;13(5):631–40. https://doi.org/10.1007/s12072-019-09969-w.
Zakeri N, Hall A, Swadling L, et al. Characterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma. Nat Commun. 2022;13(1):1372. https://doi.org/10.1038/s41467-022-29012-1.
Makkouk A, Yang XC, Barca T, et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J Immunother Cancer. 2021;9(12):e003441. https://doi.org/10.1136/jitc-2021-003441.
Xu Y, Xiang Z, Alnaggar M, et al. Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell Mol Immunol. 2021;18(2):427–39. https://doi.org/10.1038/s41423-020-0515-7.
Zimmer CL, Filipovic I, Cornillet M, et al. Mucosal-associated invariant T-cell tumor infiltration predicts long-term survival in cholangiocarcinoma. Hepatology. 2022;75(5):1154–68. https://doi.org/10.1002/hep.32222.
Duan M, Goswami S, Shi JY, et al. Activated and exhausted MAIT cells foster disease progression and indicate poor outcome in hepatocellular carcinoma. Clin Cancer Res. 2019;25(11):3304–16. https://doi.org/10.1158/1078-0432.CCR-18-3040.
Huang W, Ye D, He W, He X, Shi X, Gao Y. Activated but impaired IFN-γ production of mucosal-associated invariant T cells in patients with hepatocellular carcinoma. J Immunother Cancer. 2021;9(11):e003685. https://doi.org/10.1136/jitc-2021-003685.
Ruf B, Catania VV, Wabitsch S, et al. Activating mucosal-associated invariant T cells induces a broad antitumor response. Cancer Immunol Res. 2021;9(9):1024–34. https://doi.org/10.1158/2326-6066.CIR-20-0925.
Zheng M, Zhu J. Innate lymphoid cells and intestinal inflammatory disorders. Int J Mol Sci. 2022;23(3):1856. https://doi.org/10.3390/ijms23031856.
Tumino N, Vacca P, Quatrini L, et al. Helper innate lymphoid cells in human tumors: a double-edged sword? Front Immunol. 2020;10:3140. https://doi.org/10.3389/fimmu.2019.03140.
Chen Y, Wang X, Hao X, et al. Ly49E separates liver ILC1s into embryo-derived and postnatal subsets with different functions. J Exp Med. 2022;219(5):e20211805. https://doi.org/10.1084/jem.20211805.
Nabekura T, Riggan L, Hildreth AD, O’Sullivan TE, Shibuya A. Type 1 innate lymphoid cells protect mice from acute liver injury via interferon-γ secretion for upregulating Bcl-xL expression in hepatocytes. Immunity. 2020;52(1):96-108.e9. https://doi.org/10.1016/j.immuni.2019.11.004.
Ducimetière L, Lucchiari G, Litscher G, et al. Conventional NK cells and tissue-resident ILC1s join forces to control liver metastasis. Proc Natl Acad Sci USA. 2021;118(27):e2026271118. https://doi.org/10.1073/pnas.2026271118.
Song J, Song H, Wei H, Sun R, Tian Z, Peng H. Requirement of RORα for maintenance and antitumor immunity of liver-resident natural killer cells/ILC1s. Hepatology. 2022;75(5):1181–93. https://doi.org/10.1002/hep.32147.
Turchinovich G, Ganter S, Bärenwaldt A, Finke D. NKp46 calibrates tumoricidal potential of type 1 innate lymphocytes by regulating TRAIL expression. J Immunol. 2018;200(11):3762–8. https://doi.org/10.4049/jimmunol.1701333.
Walker JA, Oliphant CJ, Englezakis A, et al. Bcl11b is essential for group 2 innate lymphoid cell development. J Exp Med. 2015;212(6):875–82. https://doi.org/10.1084/jem.20142224.
Wang L, Tang J, Yang X, et al. TGF-β induces ST2 and programs ILC2 development. Nat Commun. 2020;11(1):35. https://doi.org/10.1038/s41467-019-13734-w.
Xu X, Ye L, Zhang Q, et al. Group-2 Innate lymphoid cells promote HCC progression through CXCL2-neutrophil-induced immunosuppression. Hepatology. 2021;74(5):2526–43. https://doi.org/10.1002/hep.31855.
He Y, Luo J, Zhang G, et al. Single-cell profiling of human CD127+ innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma. Hepatology. 2022;76(4):1013–29. https://doi.org/10.1002/hep.32444.
Crellin NK, Trifari S, Kaplan CD, Cupedo T, Spits H. Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J Exp Med. 2010;207(2):281–90. https://doi.org/10.1084/jem.20091509.
Siegler JJ, Correia MP, Hofman T, et al. Human ILC3 exert TRAIL-mediated cytotoxicity towards cancer cells. Front Immunol. 2022;13:742571. https://doi.org/10.3389/fimmu.2022.742571.
Liu Y, Song Y, Lin D, et al. NCR-group 3 innate lymphoid cells orchestrate IL-23/IL-17 axis to promote hepatocellular carcinoma development. EBioMedicine. 2019;41:333–44. https://doi.org/10.1016/j.ebiom.2019.02.050.
Hu C, Xu B, Wang X, et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology. 2022. https://doi.org/10.1002/hep.32449.
Lei X, Lei Y, Li JK, et al. Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy. Cancer Lett. 2020;470:126–33. https://doi.org/10.1016/j.canlet.2019.11.009.
Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 Suppl 1):S54-62. https://doi.org/10.1002/hep.21060.
Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359–67. https://doi.org/10.1038/s41416-020-01048-4.
Ben Khelil M, Godet Y, Abdeljaoued S, Borg C, Adotévi O, Loyon R. Harnessing antitumor CD4+ T cells for cancer Immunotherapy. Cancers (Basel). 2022;14(1):260. https://doi.org/10.3390/cancers14010260.
Zheng B, Wang D, Qiu X, et al. Trajectory and functional analysis of PD-1high CD4+CD8+ T cells in hepatocellular carcinoma by single-cell cytometry and transcriptome sequencing. Adv Sci (Weinh). 2020;7(13):2000224. https://doi.org/10.1002/advs.202000224.
Ho DW, Tsui YM, Chan LK, et al. Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma. Nat Commun. 2021;12(1):3684. https://doi.org/10.1038/s41467-021-24010-1.
Zhang S, Liu Z, Wu D, Chen L, Xie L. Single-cell RNA-seq analysis reveals microenvironmental infiltration of plasma cells and hepatocytic prognostic markers in HCC with cirrhosis. Front Oncol. 2020;10:596318. https://doi.org/10.3389/fonc.2020.596318.
Barsch M, Salié H, Schlaak AE, et al. T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. J Hepatol. 2022;77(2):397–409. https://doi.org/10.1016/j.jhep.2022.02.032.
Nguyen PHD, Wasser M, Tan CT, et al. Trajectory of immune evasion and cancer progression in hepatocellular carcinoma. Nat Commun. 2022;13(1):1441. https://doi.org/10.1038/s41467-022-29122-w.
Wang T, Dang N, Tang G, et al. Integrating bulk and single-cell RNA sequencing reveals cellular heterogeneity and immune infiltration in hepatocellular carcinoma. Mol Oncol. 2022;16(11):2195–213. https://doi.org/10.1002/1878-0261.13190.
Murai H, Kodama T, Maesaka K, et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology. 2022. https://doi.org/10.1002/hep.32573.
Xun X, Zhang C, Wang S, et al. Cyclooxygenase-2 expressed hepatocellular carcinoma induces cytotoxic T lymphocytes exhaustion through M2 macrophage polarization. Am J Transl Res. 2021;13(5):4360–75.
Sakano Y, Noda T, Kobayashi S, et al. Tumor endothelial cell-induced CD8+ T-cell exhaustion via GPNMB in hepatocellular carcinoma. Cancer Sci. 2022;113(5):1625–38. https://doi.org/10.1111/cas.15331.
Bao S, Jiang X, Jin S, Tu P, Lu J. TGF-β1 induces immune escape by enhancing PD-1 and CTLA-4 expression on T lymphocytes in hepatocellular carcinoma. Front Oncol. 2021;11:694145. https://doi.org/10.3389/fonc.2021.694145.
Song BS, Moon JS, Tian J, et al. Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion. J Immunother Cancer. 2022;10(5):e004337. https://doi.org/10.1136/jitc-2021-004337.
Hung MH, Lee JS, Ma C, et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun. 2021;12(1):1455. https://doi.org/10.1038/s41467-021-21804-1.
Huang M, Huang X, Huang N. Exosomal circGSE1 promotes immune escape of hepatocellular carcinoma by inducing the expansion of regulatory T cells. Cancer Sci. 2022;113(6):1968–83. https://doi.org/10.1111/cas.15365.
Zhang S, Gan X, Qiu J, et al. IL-10 derived from Hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment. Mol Immunol. 2021;133:163–72. https://doi.org/10.1016/j.molimm.2021.02.014.
Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72(2):250–61. https://doi.org/10.1016/j.jhep.2019.08.025.
Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol. 2016;64(1 Suppl):S84–101. https://doi.org/10.1016/j.jhep.2016.02.021.
Zhang C, Gao Y, Du C, et al. Hepatitis B-induced IL8 promotes hepatocellular carcinoma venous metastasis and intrahepatic treg accumulation. Cancer Res. 2021;81(9):2386–98. https://doi.org/10.1158/0008-5472.CAN-20-3453.
Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40(2):201-218.e9. https://doi.org/10.1016/j.ccell.2022.01.001.
Sun YF, Wu L, Liu SP, et al. Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma. Nat Commun. 2021;12(1):4091. https://doi.org/10.1038/s41467-021-24386-0.
Qin M, Wang D, Fang Y, et al. Current perspectives on B lymphocytes in the immunobiology of hepatocellular carcinoma. Front Oncol. 2021;11:647854. https://doi.org/10.3389/fonc.2021.647854.
Shao Y, Lo CM, Ling CC, et al. Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett. 2014;355(2):264–72. https://doi.org/10.1016/j.canlet.2014.09.026.
Wei Y, Lao XM, Xiao X, et al. Plasma cell polarization to the immunoglobulin G phenotype in hepatocellular carcinomas involves epigenetic alterations and promotes hepatoma progression in mice. Gastroenterology. 2019;156(6):1890-1904.e16. https://doi.org/10.1053/j.gastro.2019.01.250.
Xue H, Lin F, Tan H, Zhu ZQ, Zhang ZY, Zhao L. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4+ T cell activity in HBV-induced hepatocellular carcinoma. PLoS One. 2016;11(5):e0154815. https://doi.org/10.1371/journal.pone.0154815.
Ye L, Zhang Q, Cheng Y, et al. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion. J Immunother Cancer. 2018;6(1):145. https://doi.org/10.1186/s40425-018-0451-6.
Xiao X, Lao XM, Chen MM, et al. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov. 2016;6(5):546–59. https://doi.org/10.1158/2159-8290.CD-15-1408.
Liu RX, Wei Y, Zeng QH, et al. Chemokine (C-X-C motif) receptor 3-positive B cells link interleukin-17 inflammation to protumorigenic macrophage polarization in human hepatocellular carcinoma. Hepatology. 2015;62(6):1779–90. https://doi.org/10.1002/hep.28020.
He H, Wu J, Zang M, et al. CCR6+ B lymphocytes responding to tumor cell-derived CCL20 support hepatocellular carcinoma progression via enhancing angiogenesis. Am J Cancer Res. 2017;7(5):1151–63.
Zhang Z, Ma L, Goswami S, et al. Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma. Oncoimmunology. 2019;8(4):e1571388. https://doi.org/10.1080/2162402X.2019.1571388.
Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):396. https://doi.org/10.1186/s13046-019-1396-4.
Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016;44(5):1069–78. https://doi.org/10.1016/j.immuni.2016.04.023.
Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8. https://doi.org/10.1016/j.jhep.2013.02.022.
Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in keynote-240: a randomized, double-blind. Phase III Trial J Clin Oncol. 2020;38(3):193–202. https://doi.org/10.1200/JCO.19.01307.
Hong JY, Cho HJ, Sa JK, et al. Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial. Genome Med. 2022;14(1):1. https://doi.org/10.1186/s13073-021-00995-8.
Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90. https://doi.org/10.1016/S1470-2045(21)00604-5.
Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021;39(27):2991–3001. https://doi.org/10.1200/JCO.20.03555.
Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the checkmate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. https://doi.org/10.1001/jamaoncol.2020.4564.
Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862–73. https://doi.org/10.1016/j.jhep.2021.11.030.
Cheon J, Yoo C, Hong JY, et al. Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. Liver Int. 2022;42(3):674–81. https://doi.org/10.1111/liv.15102.
Xia Y, Tang W, Qian X, et al. Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. J Immunother Cancer. 2022;10(4):e004656. https://doi.org/10.1136/jitc-2022-004656.
Yang YL, Tsai MC, Chang YH, et al. MIR29A impedes metastatic behaviors in hepatocellular carcinoma via targeting LOX, LOXL2, and VEGFA. Int J Mol Sci. 2021;22(11):6001. https://doi.org/10.3390/ijms22116001.
Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960–70. https://doi.org/10.1200/JCO.20.00808.
Ho WJ, Zhu Q, Durham J, et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat Cancer. 2021;2(9):891–903. https://doi.org/10.1038/s43018-021-00234-4.
Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2017;66(3):545–51. https://doi.org/10.1016/j.jhep.2016.10.029.
Zhang S, Zhao Y, He L, et al. Effect of camrelizumab plus transarterial chemoembolization on massive hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2022;46(4):101851. https://doi.org/10.1016/j.clinre.2021.101851.
Chiang CL, Chan ACY, Chiu KWH, Kong FS. Combined stereotactic body radiotherapy and checkpoint inhibition in unresectable hepatocellular carcinoma: a potential synergistic treatment strategy. Front Oncol. 2019;9:1157. https://doi.org/10.3389/fonc.2019.01157.
Greco B, Malacarne V, De Girardi F, et al. Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies. Sci Transl Med. 2022;14(628):eabg3072. https://doi.org/10.1126/scitranslmed.abg3072.
Zheng X, Liu X, Lei Y, Wang G, Liu M. Glypican-3: a novel and promising target for the treatment of hepatocellular carcinoma. Front Oncol. 2022;12:824208. https://doi.org/10.3389/fonc.2022.824208.
Dai H, Tong C, Shi D, et al. Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial. Oncoimmunology. 2020;9(1):1846926. https://doi.org/10.1080/2162402X.2020.1846926.
Shi D, Shi Y, Kaseb AO, et al. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: results of phase I trials. Clin Cancer Res. 2020;26(15):3979–89. https://doi.org/10.1158/1078-0432.CCR-19-3259.
Liu X, Gao F, Jiang L, et al. 32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma. J Transl Med. 2020;18(1):295. https://doi.org/10.1186/s12967-020-02462-1.
Batra SA, Rathi P, Guo L, et al. Glypican-3-specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma. Cancer Immunol Res. 2020;8(3):309–20. https://doi.org/10.1158/2326-6066.CIR-19-0293.
Caraballo Galva LD, Jiang X, Hussein MS, et al. Novel low-avidity glypican-3 specific CARTs resist exhaustion and mediate durable antitumor effects against HCC. Hepatology. 2022;76(2):330–44. https://doi.org/10.1002/hep.32279.
Huang Y, Zeng J, Liu T, Xu Q, Song X, Zeng J. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. Cancer Manag Res. 2020;12:3247–55. https://doi.org/10.2147/CMAR.S253565.
Garofano F, Sharma A, Abken H, Gonzalez-Carmona MA, Schmidt-Wolf IGH. A low dose of pure cannabidiol is sufficient to stimulate the cytotoxic function of CIK Cells without exerting the downstream mediators in pancreatic cancer cells. Int J Mol Sci. 2022;23(7):3783. https://doi.org/10.3390/ijms23073783.
Rong XX, Wei F, Lin XL, et al. Recognition and killing of cancer stem-like cell population in hepatocellular carcinoma cells by cytokine-induced killer cells via NKG2d-ligands recognition. Oncoimmunology. 2015;5(3):e1086060. https://doi.org/10.1080/2162402X.2015.1086060.
Yu SJ, Ma C, Heinrich B, et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J Hepatol. 2019;70(3):449–57. https://doi.org/10.1016/j.jhep.2018.10.040.
Huang ZM, Lai CX, Zuo MX, et al. Adjuvant cytokine-induced killer cells with minimally invasive therapies augmented therapeutic efficacy of unresectable hepatocellular carcinoma. J Cancer Res Ther. 2020;16(7):1603–10. https://doi.org/10.4103/jcrt.JCRT_962_19.
Ji Q, Fu Y, Zhu X, Wang L, Ling C. Effect of RFA and TACE combined with postoperative cytokine-induced killer cell immunotherapy in primary hepatocellular carcinoma. J BUON. 2021;26(1):235–42.
Lee JH, Lee JH, Lim YS, et al. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol Immunother. 2019;68(1):23–32. https://doi.org/10.1007/s00262-018-2247-4.
Cho JY, Kwon SH, Lee EK, Lee JH, Kim HL. Cost-effectiveness of adjuvant immunotherapy with cytokine-induced killer cell for hepatocellular carcinoma based on a randomized controlled trial and real-world data. Front Oncol. 2021;11:728740. https://doi.org/10.3389/fonc.2021.728740.
Chen CL, Pan QZ, Zhao JJ, et al. PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Oncoimmunology. 2016;5(7):e1176653. https://doi.org/10.1080/2162402X.2016.1176653.
Chang B, Shen L, Wang K, et al. High number of PD-1 positive intratumoural lymphocytes predicts survival benefit of cytokine-induced killer cells for hepatocellular carcinoma patients. Liver Int. 2018;38(8):1449–58. https://doi.org/10.1111/liv.13697.
Yu R, Zhu B, Chen D. Type I interferon-mediated tumor immunity and its role in immunotherapy. Cell Mol Life Sci. 2022;79(3):191. https://doi.org/10.1007/s00018-022-04219-z.
Llovet JM, Sala M, Castells L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000;31(1):54–8. https://doi.org/10.1002/hep.510310111.
Chen LT, Chen MF, Li LA, et al. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg. 2012;255(1):8–17. https://doi.org/10.1097/SLA.0b013e3182363ff9.
Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Müllhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg. 2009;96(9):975–81. https://doi.org/10.1002/bjs.6731.
Hou J, Zhou Y, Zheng Y, et al. Hepatic RIG-I predicts survival and interferon-α therapeutic response in hepatocellular carcinoma. Cancer Cell. 2014;25(1):49–63. https://doi.org/10.1016/j.ccr.2013.11.011.
Yang Y, Zhou Y, Hou J, et al. Hepatic IFIT3 predicts interferon-α therapeutic response in patients of hepatocellular carcinoma. Hepatology. 2017;66(1):152–66. https://doi.org/10.1002/hep.29156.
Hu B, Yu M, Ma X, et al. IFNα potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment. Cancer Discov. 2022;12(7):1718–41. https://doi.org/10.1158/2159-8290.CD-21-1022.
Liao J, Zeng DN, Li JZ, et al. Type I IFNs repolarized a CD169+ macrophage population with anti-tumor potentials in hepatocellular carcinoma. Mol Ther. 2021;30(2):632–43. https://doi.org/10.1016/j.ymthe.2021.09.021.
Zhang Z, Zhu Y, Xu D, et al. IFN-α facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma. Am J Transl Res. 2021;13(1):301–13.
Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525–43. https://doi.org/10.1038/s41575-021-00438-0.
Taniguchi M, Mizuno S, Yoshikawa T, et al. Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis. Cancer Sci. 2020;111(8):2747–59. https://doi.org/10.1111/cas.14497.
Yu L, Huang N, Sun H, et al. Development of a tetravalent T-cell engaging bispecific antibody against glypican-3 for hepatocellular carcinoma. J Immunother. 2021;44(3):106–13. https://doi.org/10.1097/CJI.0000000000000349.
Silva L, Egea J, Villanueva L, et al. Cold-inducible RNA binding protein as a vaccination platform to enhance immunotherapeutic responses against hepatocellular carcinoma. Cancers (Basel). 2020;12(11):3397. https://doi.org/10.3390/cancers12113397.
Chen K, Wu Z, Zhao H, et al. XCL1/Glypican-3 fusion gene immunization generates potent antitumor cellular immunity and enhances anti-PD-1 efficacy. Cancer Immunol Res. 2020;8(1):81–93. https://doi.org/10.1158/2326-6066.CIR-19-0210.
Ikeda M, Okusaka T, Ohno I, et al. Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma. Immunotherapy. 2021;13(5):371–85. https://doi.org/10.2217/imt-2020-0278.
Bai X, Zhou Y, Yokota Y, et al. Adaptive antitumor immune response stimulated by bio-nanoparticle based vaccine and checkpoint blockade. J Exp Clin Cancer Res. 2022;41(1):132. https://doi.org/10.1186/s13046-022-02307-3.
Liu Z, Lu Z, Jing R, et al. Alarmin augments the antitumor immunity of lentiviral vaccine in ectopic, orthotopic and autochthonous hepatocellular carcinoma mice. Theranostics. 2019;9(14):4006–18. https://doi.org/10.7150/thno.32720.
Li Z, Ding J, Zhao X, Qi G. Combination therapy of hepatocellular carcinoma by DNA shuffling-based VEGF vaccine and doxorubicin. Immunotherapy. 2018;10(11):951–69. https://doi.org/10.2217/imt-2017-0194.
Yu J, Sun H, Cao W, Song Y, Jiang Z. Research progress on dendritic cell vaccines in cancer immunotherapy. Exp Hematol Oncol. 2022;11(1):3. https://doi.org/10.1186/s40164-022-00257-2.
Lee JH, Tak WY, Lee Y, et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology. 2017;6(7):e1328335. https://doi.org/10.1080/2162402X.2017.1328335.
Han CL, Yan YC, Yan LJ, et al. Efficacy and security of tumor vaccines for hepatocellular carcinoma: a systemic review and meta-analysis of the last 2 decades. J Cancer Res Clin Oncol. 2022. https://doi.org/10.1007/s00432-022-04008-y.
Vogt A, Sadeghlar F, Ayub TH, et al. Alpha-fetoprotein- and CD40Ligand-expressing dendritic cells for immunotherapy of hepatocellular carcinoma. Cancers (Basel). 2021;13(13):3375. https://doi.org/10.3390/cancers13133375.
Pang YB, He J, Cui BY, et al. A potential antitumor effect of dendritic cells fused with cancer stem cells in hepatocellular carcinoma. Stem Cells Int. 2019;2019:5680327. https://doi.org/10.1155/2019/5680327.
Wang Y, Zhao Q, Zhao B, et al. Remodeling tumor-associated neutrophils to enhance dendritic cell-based HCC neoantigen nano-vaccine efficiency. Adv Sci (Weinh). 2022;9(11):e2105631. https://doi.org/10.1002/advs.202105631.
Teng CF, Wang T, Shih FY, Shyu WC, Jeng LB. Therapeutic efficacy of dendritic cell vaccine combined with programmed death 1 inhibitor for hepatocellular carcinoma. J Gastroenterol Hepatol. 2021;36(7):1988–96. https://doi.org/10.1111/jgh.15398.
Teng CF, Wang T, Wu TH, et al. Combination therapy with dendritic cell vaccine and programmed death ligand 1 immune checkpoint inhibitor for hepatocellular carcinoma in an orthotopic mouse model. Ther Adv Med Oncol. 2020;12:1758835920922034. https://doi.org/10.1177/1758835920922034.
Jung NC, Lee JH, Choi HJ, et al. Dendritic cell immunotherapy combined with cytokine-induced killer cells effectively suppresses established hepatocellular carcinomas in mice. Immunol Invest. 2016;45(6):553–65. https://doi.org/10.1080/08820139.2016.1183025.
Peng S, Chen S, Hu W, et al. Combination neoantigen-based dendritic cell vaccination and adoptive T-cell transfer induces antitumor responses against recurrence of hepatocellular carcinoma. Cancer Immunol Res. 2022;10(6):728–44. https://doi.org/10.1158/2326-6066.CIR-21-0931.
Liu TC, Kirn D. Systemic efficacy with oncolytic virus therapeutics: clinical proof-of-concept and future directions. Cancer Res. 2007;67(2):429–32. https://doi.org/10.1158/0008-5472.CAN-06-2871.
Liu JKH, Irvine AF, Jones RL, Samson A. Immunotherapies for hepatocellular carcinoma. Cancer Med. 2022;11(3):571–91. https://doi.org/10.1002/cam4.4468.
Moehler M, Heo J, Lee HC, et al. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). Oncoimmunology. 2019;8(8):1615817. https://doi.org/10.1080/2162402X.2019.1615817.
Lei G, Li B, Yang H, et al. Therapeutic efficacy of an oncolytic influenza virus carrying an antibody against programmed cell death 1 in hepatocellular carcinoma. Hum Gene Ther. 2022;33(5–6):309–17. https://doi.org/10.1089/hum.2021.167.
Lei GL, Wang LP, Dong SH, et al. A recombinant influenza virus with a CTLA4-specific scFv inhibits tumor growth in a mouse model. Cell Biol Int. 2021;45(6):1202–10. https://doi.org/10.1002/cbin.11559.
Deng L, Yang X, Ding Y, et al. Oncolytic therapy with vaccinia virus carrying IL-24 for hepatocellular carcinoma. Virol J. 2022;19(1):44. https://doi.org/10.1186/s12985-022-01779-1.
Jiang R, Qiu Y, Zhang X, et al. Oncolytic vaccinia virus harboring aphrocallistes vastus lectin inhibits the growth of hepatocellular carcinoma cells. Mar Drugs. 2022;20(6):378. https://doi.org/10.3390/md20060378.
Liu L, You X, Han S, Sun Y, Zhang J, Zhang Y. CD155/TIGIT, a novel immune checkpoint in human cancers (Review). Oncol Rep. 2021;45(3):835–45. https://doi.org/10.3892/or.2021.7943.
Zhang H, Zhang Y, Dong J, et al. Recombinant adenovirus expressing the fusion protein PD1PVR improves CD8+ T cell-mediated antitumor efficacy with long-term tumor-specific immune surveillance in hepatocellular carcinoma. Cell Oncol (Dordr). 2021;44(6):1243–55. https://doi.org/10.1007/s13402-021-00633-w.
Zhang Z, Krimmel J, Zhang Z, Hu Z, Seth P. Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model. Hum Gene Ther. 2011;22(9):1137–42. https://doi.org/10.1089/hum.2011.003.
Hong J, Yun CO. Overcoming the limitations of locally administered oncolytic virotherapy. BMC Biomed Eng. 2019;1:17. https://doi.org/10.1186/s42490-019-0016-x.
Garofalo M, Bellato F, Magliocca S, et al. Polymer coated oncolytic adenovirus to selectively target hepatocellular carcinoma cells. Pharmaceutics. 2021;13(7):949. https://doi.org/10.3390/pharmaceutics13070949.
Acknowledgements
The authors thank all the workshop participants and Fazhi Xiong, Rui Zhao, and Huaxing Ma for their help with the work.
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The work was supported by the National Natural Science Foundation of China (No. 82260535), the National Natural Science Foundation (Cultivation Project of General Program) of Guizhou Medical University (No. gyfynsfc-2022-07), and the National Natural Science Foundation of China (NSFC) Cultivation Program of Affiliated Hospital of Guizhou Medical University (No. gyfynsfc-2021-34).
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Gao, X., Zuo, S. Immune landscape and immunotherapy of hepatocellular carcinoma: focus on innate and adaptive immune cells. Clin Exp Med 23, 1881–1899 (2023). https://doi.org/10.1007/s10238-023-01015-2
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DOI: https://doi.org/10.1007/s10238-023-01015-2