Abstract
Hematological malignancies (HM) are common malignant tumors with high morbidity and mortality rates, and are malignant diseases that seriously affect human health, with chemotherapy prone to recurrence and toxic side effects. Therefore, the development of precise, effective, and safe targeted therapeutic agents has become a hotspot in the current research of antitumor technology. More and more studies have shown that the interaction of C–C chemokine ligand 17 (CCL17) and C–C chemokine ligand 22 (CCL22) with the receptor C–C chemokine receptor type 4 (CCR4) promotes the immune escape of tumors and is closely related to the occurrence, development, and prognosis of hematological tumors. In this regard, we present a review on the expression and role of the CCL17/CCL22-CCR4 axis in HM, including lymphoma, leukemia, and multiple myeloma, with the aim of providing latest ideas and directions for the diagnosis and treatment of HM. In addition, we discuss the role and related mechanisms of HM therapeutic agents targeting the CCL17/CCL22-CCR4 axis and the potential of humanized anti-CCR4 antibodies for the treatment of HM.
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1 Introduction
In recent years, tumor microenvironment (TME) has become a hot direction in tumor research. TME plays a key role in supporting tumor growth, regulating immune surveillance of tumor cells, and promoting immune escape [1]. TME consists of tumor cells, vascular system, extracellular matrix (ECM) cells, stromal cells (e.g., fibroblasts, mesenchymal cells, adipocytes), and natural and adaptive immune cells [2, 3] (Fig. 1). The activity of TME components is regulated by a variety of immunomodulatory factors (e.g. cytokines, chemokines and growth factors) [1]. Among them, chemokine members-CC chemokine 17 (CCL17) and CC chemokine 22 (CCL22)-play important roles in TME, which is currently a hot research topic in the field of oncology.
The composition of the TME. TME tumor microenvironment, NK Natural killer, Treg Regulatory T cell, TAN Tumor-associated neutrophil, TAM Tumor-associated macrophage, ECM Extracellular matrix, CAF Cancer-associated fibroblast. The TME plays a key role in supporting tumor growth, regulating immune surveillance of tumor cells, and facilitating immune escape. The TME consists of tumor cells, the vascular system, ECM cells, stromal cells (e.g., fibroblasts, mesenchymal stromal cells, adipocytes), and natural and adaptive immune cells. Among them, natural and adaptive immune cells include lymphocytes (e.g., T cells, NK cells, B cells), dendritic Cells, neutrophils, and macrophages. Tregs are a subpopulation of CD4+ T cells that control peripheral immune tolerance as well as responses to foreign antigens and tumor antigens
Hematological malignancies (HM) are a group of malignant diseases of the blood system including leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes, etc., which are characterized by a high degree of malignancy, complexity of treatment, poor prognosis, etc. [4]. HM is mostly treated with radiotherapy, chemotherapy, and bone marrow transplantation, but HM has high recurrence and mortality rates. Therefore, the treatment of HM still has great challenges [5]. A growing number of studies have shown that the expression and role of CCR4 and its ligands CCL17 and CCL22 in HM are closely related to the pathogenesis and therapeutic response of HM [6, 7]. Therefore, it is particularly important to clarify the CCL17/CCL22-CCR4 axis in HM to provide new targets and theoretical basis for the treatment of HM.
This article provides a brief review of the research progress on the expression and role of CCR4 and its ligands CCL17/CCL22 in HM, aiming to provide latest ideas and directions for the diagnosis and treatment of hematologic tumors.
2 Overview of the chemokines CCL17 and CCL22 and their receptor CCR4
Chemokines are a class of small-molecule proteins secreted by cells and are important components of the TME [8]. After binding to their receptors, chemokines mainly act on the migration of leukocytes, such as monocytes, eosinophils, and dendritic cells. In addition, chemokines can affect the proliferation, invasion and metastasis of tumor cells and promote tumor progression [9].
C–C chemokine ligand 17 (CCL17), also known as Thymus activation regulating chemokine (TARC), belongs to the C–C chemokine family member [10]. CCL17 is produced by dendritic cells, endothelial cells, keratinocytes, and fibroblasts and is highly expressed in the thymus, where it plays an important role in T-cell development, trafficking, and activation of mature T cells [11]. C–C chemokine ligand 22 (CCL22), also known as Macrophage-derived chemokine (MDC), is expressed in dendritic cells, macrophages, and activated monocytes [10]. Mature CCL22 induces chemotaxis or Ca2+ activation in NK cells, activated T lymphocytes and dendritic cells [12]. In TME, tumor-associated macrophages (TAMs) and tumor cells produce CCL17 and CCL22 [13, 14]. In addition, cancer-associated fibroblasts (CAFs) and tumor-associated neutrophils (TANs) can produce CCL17 [15, 16]. C–C chemokine receptor type 4 (CCR4), also designated CD194, is a receptor that is specific for the chemokines CCL17 and CCL22. CCR4 is expressed on T-lymphocytes (Th2, Th17, Th22 cells, and Tregs), skin homing T-cells, lung homing T-cells, platelets, NK cells, monocytes, macrophages, and DCs [17, 18].
In TME, CCL17 and CCL22 bind to CCR4 on cells such as Tregs and Th17 cells. This results in the attraction of additional cells, including Tregs and Th17 cells, which in turn creates an immunosuppressive microenvironment that is favorable to the survival and growth of tumor cells [19]. However, CCL17/CCL22-CCR4 also induces tumor infiltrating lymphocyte (TIL) infiltration into tumors and has anticancer effects [20]. As the biological mechanisms underlying the CCL17/CCL22-CCR4 axis become increasingly understood, it may prove a valuable therapeutic target for the treatment of allergies, autoimmune deficiencies and malignant neoplasms. The utilization of small molecule compounds and antibodies with the capacity to inhibit CCL17- and CCL22-mediated recruitment of Th2 cells and Tregs has been evidenced to engender favorable outcomes in a multitude of disease models, including asthma, atopic disease and tumor growth [21].
3 Expression of the chemokines CCL17 and CCL22 and their receptor CCR4 in lymphoma
3.1 Hodgkin lymphoma
3.1.1 Classic Hodgkin lymphoma
Classic Hodgkin Lymphoma (CHL) is a B-cell tumor characterized by Reed-Sternberg cells (R-S cells) [22]. R-S cells secrete a large number of chemokines and cytokines, including CCL5, CCL17, CCL22, and several interleukins. CCL17 and CCL22 specifically bind to CCR4 expressed on Tregs and Th2 cells, which recruits Th2 cells and Tregs into the CHL microenvironment [23]. Studies have shown that these recruited Th2 cells can secrete IL-4, IL-5, and IL-13, IL4 regulates lymphocyte differentiation, proliferation, and survival through the JAK/STAT6 or STAT3 and IRS-1/IRS-2/AKT pathways, and activation of STAT6 in R-S cells further increases CCL17 secretion [24, 25]. The expression of CCL17 and CCL22 in HM cells is summarized in Table 1.
Studies have shown that plasma and serum CCL17 expression levels are elevated in children with CHL and significantly decreased after one cycle of chemotherapy [23]. However, a recent study found that low expression of CCL17 on R-S cells was associated with treatment failure [38]. Studies have confirmed that CCL17 is a highly sensitive and specific diagnostic, early progression, and prognostic biomarker in pediatric patients with CHL, that CCL17 is more specific than radiologic evaluation, and that the cost of CCL17 testing is much lower than radiologic evaluation, and that it may be of value as a screening test in the examination of pediatric patients with enlarged lymph nodes [23, 39, 40]. Plasma CCL17 has been reported to be more discriminatory than serum CCL17 in CHL patients with disease progression and complete response (CR). Therefore, the use of plasma CCL17 is recommended for disease monitoring [23]. However, a limitation of this study is the small number of CHL cases with disease progression, and larger studies are necessary to draw conclusions about CCL17 as a marker of long-term progression-free survival.
In adult CHL, CCL17 is expressed in lymph node biopsies in approximately 90%-95% of cases [7]. In a study, CCL17 levels were observed to be elevated in 90% of untreated CHL patients in comparison to healthy individuals. Following the administration of an efficacious treatment regimen, a notable decline in CCL17 levels was documented [41]. Moreover, evidence indicates that elevated levels of CCL17 following treatment are linked to diminished survival rates [42]. A reduction in CCL17 levels following a single cycle of chemotherapy has been observed to correlate with an progression-free survival [7]. Serum CCL17 levels that are consistently high have been linked to the development of subsequent diseases [40]. A multicenter study examined serum levels of nine chemokines in 163 untreated HL patients and 334 controls. The results showed that serum CCL17 and CCL22 levels were significantly elevated in 82% and 57% of HL patients. Serum CCL17 and CCL22 levels were elevated in cases of tuberous sclerosis (P < 0.001), and serum levels correlated with Ann Arbor staging. Most of the nine patients whose serum samples were taken before and after treatment showed lower levels of CCL17 and CCL22. In 74 cases, HRS cells expressed 77% and 75% of CCL17 and CCL22, respectively [43]. Therefore, serum CCL17 level is not only a marker but also a possible predictor of CHL treatment response. Studies have indicated a positive relationship between tumor load and Ann Arbor staging, as well as serum CCL17 levels. Furthermore, compared to patients with low metabolic tumor volume (MTV), those with high MTV exhibited noticeably higher serum CCL17 levels. On the other hand, patients with more or fewer lesions did not significantly differ in their serum CCL17 levels [44]. Some studies have shown that CCL17 test may be superior to PET-CT in the assessment and monitoring of CHL and has the advantages of no radiation and low cost. It is considered to be an alternative to PET-CT for mid-term response assessment, which is conducive to early identification of CHL patients at risk of treatment failure, timely adjustment of treatment regimens, and improvement of patient prognosis [41]. FDG-PET imaging is now the gold standard for midterm response assessment in CHL patients [45]. Recent studies have confirmed that CCL17 may be complementary to FDG-PET in predicting treatment response, but the combination of FDG-PET and CCL17 in prognostic models needs to be explored further [44]. Recent studies have demonstrated that nude mouse tumor models show that CCL17 mobilizes NK cells to inhibit lymphoma growth and enhances NK-cDC1 interactions to counteract IL4i1-mediated immunosuppression. Interestingly, the CCL17-mediated anti-tumor immune response was mainly dependent on lymphoid lineage cells rather than myeloid cells [46].
In summary, R-S cells secrete large amounts of CCL17/CCL22, which bind to the receptor CCR4 and recruit Th2 cells and Tregs to the TME, and Th2 cells can secrete IL-4, IL-5, and IL-13, which activate the JAK/STAT signaling pathway and further increase the secretion of CCL17. CCL17 can be used as a biomarker of CHL in children and adults marker and may be considered as an alternative to radiologic imaging for response assessment, but further exploration is needed.
3.1.2 Others
Early studies have found that CCL22 is expressed in cases of nodular lymphocyte predominance Hodgkin lymphoma (NLPHL) [47]. Melvin et al. found immunohistochemical detection of CCL17 to be valuable in identifying CHL and its similar diseases, including NLPHL, reactive lymphadenopathy, and mature lymphoid tumors with R-S-like cells [22].
3.2 Non-Hodgkin lymphoma
3.2.1 Diffuse large B-cell lymphomas
Diffuse large B-cell lymphomas (DLBCL) are the most common lymphoid malignancy in adults, accounting for almost 30% of all cases of non-Hodgkin lymphoma (NHL) [48]. Epstein-Barr virus (EBV)-positive DLBCL with chronic inflammation (DLBCL-CI) occurs in patients with chronic inflammation but without any predisposing immunodeficiency. EBV-positive Pyothorax-associated lymphoma (PAL) is the prototype of DLBCL-CI [49]. Higuchi et al. showed that PAL cell lines expressed and secreted the chemokines CCL17 and CCL22 compared to EBV-negative DLBCL cell lines, and culture supernatants of PAL cell lines attracted CCR4+ Tregs from human peripheral blood mononuclear cells. CCL17 expression was co-regulated by the p38/ATF2 and TRAF/NF-κB signaling pathways, while CCL22 expression was mainly mediated by either signaling pathway in PAL cell lines. regulation, whereas CCL22 expression was mediated primarily by either signaling pathway in the PAL cell line. CCL17 and CCL22 as well as CCR4+ Tregs were strongly positively expressed in primary PAL tissues [26].
EBV major latent membrane protein 1 (LMP1) is a transmembrane protein that, in the absence of ligand, structurally activates NF-κB, p38, JNK, MAPK, PI3K, IRF7 and STAT signaling pathways [50,51,52]. Overexpression of the chemokines CCL17 and CCL22 is an important marker of LMP1-mediated NF-κB activation, which has been demonstrated in vitro and in vivo. Inhibitors of NF-κB and STAT inhibit the viral oncogene LMP1 and cell survival [27, 53]. It was found that LMP1-expressing B-cell lymphoma-derived cell lines secreted CCL17 and CCL22 at high levels in vitro. Reducing the mRNA level of LMP1 in these cell lines by small interfering RNA (siRNA) decreased the expression of CCL17 and CCL22. In addition, although expression of Latent membrane protein 2A (LMP2A) is not sufficient to express CCL17 and CCL22 in EBV-infected B cells, it has been shown to cooperate with LMP1 for its activity and also affects the production of CCL17 and CCL22 [28]. It has been demonstrated that LMP1 is induced by activation of the TRAF/NF-κB and p38/ATF2 pathways to induce the expression of CCL17 and CCL22, and that the production of CCL17 and CCL22 recruits Th2 cells and Tregs, which may contribute to the evasion of immunosurveillance of EBV-infected B cells from Th1 cells [27].
A different subtype of DLBCL is called primary mediastinal large B cell lymphoma (PMBCL). Mutation of IL4R (p. I242N mutation) leading to gain-of-function and loss-of-function of protein tyrosine phosphatase non-receptor type 1 (PTPN1). It was discovered that the JAK-STAT pathway increased the expression of CCL17 in PMBCL [54].
3.2.2 Follicular lymphoma
The pathophysiology and course of follicular lymphoma (FL), an incurable B-cell NHL, are significantly influenced by the microenvironment [55]. It has been demonstrated that follicular Th cells (TFH) produce IL-4, which is elevated in the TME of FL. IL-4 also promotes the active recruitment of Tregs and IL-4-producing T cells, which in turn stimulates more CCL17 production. Finally, IL-4 induces CCL17 production through autocrine and paracrine effects on intratumoral T cells and tumor cells, respectively. Furthermore, STAT6 is activated by IL-4 to produce CCL17, and siRNA knockdown of STAT6 prevents this process [29]. The germinal center (GC), where B cells and T cells converge, is home to the CD40-CD40L pathway, which is essential for B cell survival, proliferation, and plasma cell differentiation [56]. It was discovered that TFH expressed CD40L, which caused FL tumor cells to produce CCL17 and CCL22. Furthermore, IL-4 amplified CD40L's stimulatory effect on CCL17 and CCL22. An immunosuppressive TME that supports tumor immune evasion, tumor cell survival, and growth is created when CCL17 and CCL22 overexpression in the TME attracts Tregs and IL4-expressing T cells, which in turn stimulates increased chemokine production [30]. Thus, depletion of TFH-expressed IL-4 and CD40L may inhibit FL tumor cell survival and growth. A recent study found that idelalisib interfered with FL-T cell crosstalk via CD40/CD40L and remodeled the FL immune microenvironment by affecting Tregs and TFH recruitment through downregulation of CCL22 [31].
The PI3K-δ inhibitor idelalisib has been approved as monotherapy for recurrent FL. It was found that idelalisib downregulated CCL22, blocked CCL22-induced AKT phosphorylation, hindered TFH and Tregs recruitment, and remodeled the FL immune microenvironment [57]. SHC014748M is a highly selective PI3K-δ inhibitor, and serum CCL17 and CCL22 levels were significantly decreased in NHL patients treated with SHC014748M. In addition, in vivo studies showed that SHC014748M significantly inhibited the growth of lymphoma cells and had stronger anti-tumor activity than idelalisib against NHL [58]. Therefore, SHC014748M may be a novel drug for the treatment of NHL. Tazemetostat, a histone-lysine N-methyltransferase enzyme (EZH2) inhibitor, has been approved in Japan for the treatment of patients with EZH2 functionally acquired mutations in FL [59]. It has been shown that the CCL17 promoter region is enriched in inhibitory histone modified H3K27me3. Tazemetostat enhances CCL17 promoter activity by inhibiting EZH2 leading to H3K27me3 demethylation, which promotes the secretion of CCL17 from B-cell lymphomas, activates the anti-lymphoma response and promotes the migration of potentially cytotoxic T-cells, which can be toxic to Lymphoma cells with toxic effects [60]. However, this was mainly based on experiments with cell lines, so further analysis is necessary to see if EZH2 inhibitors function to upregulate CCL17 expression levels and increase tumor-infiltrating T cells in patients with B-cell lymphoma.
3.2.3 Cutaneous T-cell lymphoma
Cutaneous T-cell lymphoma (CTCL) is a rare group of extranodal non-Hodgkin lymphomas (NHL), Mycosis fungoides (MF) and Sézary syndrome (SS) are two subtypes of CTCL. SS) are two subtypes of CTCL[61]. Studies have shown that TME plays a significant role in the pathogenesis of MF/SS [62].
Studies have shown that CCL17 can be used as a diagnostic marker for CTCL [63]. CCR4 is widely expressed in tumor cells, malignant T cells, and Tregs in the skin and peripheral blood of patients with MF and SS. CCR4 is elevated at all stages of CTCL and increases with disease progression [64]. The relative expression levels of CCR4 in two CTCL cell lines (MJ cells and Hut78 cells), and human leukemia cell line (Jurkat cells) were detected and compared by applying real-time fluorescence quantitative PCR (qPCR) and flow cytometry. Hut78 cells and control cells (Jurkat cells). Since MJ cells were derived from MF patients and Hut78 cells were derived from SS patients, the differential expression of CCR4 on MJ and Hut78 cells seems to further confirm the important role of CCR4 in CTCL skin homing [32]. Currently, CCR4 has been identified as an important target for treating CTCL [65]. In addition, an increase in the number of CCR4 + malignant T cells was associated with a poor prognosis for the disease [66]. This provides further evidence that CCR4 is a significant biomarker of the progression of the disease and the potential for a therapeutic target. It has been demonstrated that, in cases of CTCL, the expression of the CCR4 is enhanced as a consequence of elevated activity of the transcription factor FRA-2 [67].
It has been demonstrated that CCL17 and CCL22 are overexpressed in the skin of patients with MF or SS, where they interact with CCR4 to facilitate the migration and accumulation of CCR4+ T cells in the skin [61]. It was shown that enhanced expression of CCL22 in Langerhans cells (LC) in the epidermis of CTCL lesions mediated the localization and aggregation of CCR4+ malignant T cells in the skin, leading to the formation of Pautrier microabscesses typical of MF [33]. In the initial stages of CTCL, there is a notable increase in the expression of the chemokines CXCL9 and CXCL10 by keratinocytes (KCs) and dermal fibroblasts in the affected skin. This results in the attraction of Th1 cells to the site of inflammation. However, in advanced CTCL, the expression level of Th1 cell-associated chemokines was significantly decreased, while the expression of chemokines CCL17 and CCL22, which attract Th2 cells, was increased [68, 69]. Recombinant thymic stromal lymphopoietin (TSLP) is a cytokine that activates CD11c-positive dendritic cells and initiates Th2-type immune responses and inflammation through the synthesis of chemokines that are associated with the Th2 immune response, such as CCL17 and CCL22 [70]. The concentration of TSLP in serum and plasma was found to be elevated in patients with CTCL in comparison to healthy controls. This observation suggests that the Th2-dominant environment observed in CTCL lesions may be driven by TSLP [68]. Additionally, CCL17 and CCL22 have been observed to recruit CCR4 + Tregs, immunosuppressive macrophages and NK cells into the TME. This recruitment facilitates the evasion of malignant T cells from normal immune surveillance and the proliferation of tumor cells, which play a crucial role in the onset and progression of CTCL [71]. CCL17 and CCL22 increase malignant T cell survival in an in vitro study of cells from MF patients [32]. This further supports the importance of the CCL17/CCL22-CCR4 axis in the pathophysiology of CTCL and its validity as a therapeutic target for CTCL. It has been shown that CCL17 is produced by DCs, endothelial cells, keratinocytes and fibroblasts, and helps to recognize malignant T cells in the blood that express CCR4 and cutaneous lymphocyte antigen (CLA) and promotes their attachment to the endothelial surface [72]. CCL22 is produced by DC and M2 macrophages and synergizes with CCL17 [73].
Cronshaw et al. showed that CCL22 can induce more sustained Akt phosphorylation than CCL17 in Th2 cells [74]. The chemotaxis assay showed that CCL22 had a higher chemotaxis capacity for MJ cells than Hut78 cells and control cells (Jurkat cells). CCL17 also induced chemotaxis of MJ cells in a dose-dependent manner, but to a lesser extent than CCL22. In addition, CCL22 was superior to CCL17 in facilitating transendothelial migration of MJ cells [32]. These findings may facilitate the development of anti-CCR4 agents that selectively target CCL22 rather than CCL17 for the treatment of CTCL. NF-kB activity regulates the expression of chemokines CCL17 and CCL2, and CCL17 and CCL22 may provide a survival advantage by activating the JAK/STAT pathway [75]. STAT6 is a major factor in MF/SS tumorigenesis and promotes the proliferation and invasion of malignant lymphocytes, thereby suppressing anti-tumor immune responses. Gaydosik et al. performed transcriptomic analysis of the whole genome of STAT6-regulated genes in advanced CTCL and found that STAT6 controls the expression of the CCL17 gene, and that inhibition of STAT6 downregulates the expression of the CCL17 gene. Therefore, targeting STAT6 may become a new therapeutic approach for MF/SS [76].
Bexarotene is a high-affinity specific retinoid X receptor (RXR) agonist approved for the treatment of early and advanced CTCL [77]. Tanita et al. showed that serum CCL22 levels were significantly reduced in 80% of CTCL patients who were effective on Bexarotene treatment, but not in CTCL patients who did not respond to Bexarotene. This suggests that CCL22 can be used as a biomarker to evaluate the efficacy of Bexarotene in the treatment of CTCL [78]. IFN-α and IFN-γ are effective treatments for advanced MF, and cellular experiments demonstrated that mRNA expression of CCL17 and CCL22 was significantly reduced after stimulation with IFN-α and IFN-γ [79]. ELISA detected a significant decrease in the amount of chemokine CCL17 protein secreted by M2 macrophages after 48 h of IFN-α or IFN-γ stimulation, with no effect on the secretion of CCL22 protein [80]. This study demonstrates that IFN-α and IFN-γ inhibit lymphoma cell recruitment in the skin by inhibiting CCL17 production by M2 macrophages.
3.2.4 Peripheral T-cell lymphoma
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of clinically aggressive diseases with a poor prognosis [81]. Angioimmunoblastic T Cell Lymphoma (AITL) is now considered a separate subtype of PTCL [82]. 30–50% of AITL patients present with blood hyper eosinophilia [83]. Eosinophils in AITL tumor biopsy tissue were found to correlate with mRNA expression levels of CCL17 in tumor-infiltrating single nucleated cells [84]. It is unclear whether the tumor cells themselves favor eosinophilia or whether locally produced CCL17 attracts tumor infiltrating responsive Th2 cells [85]. Spatial transcriptional analysis revealed that the expression of CCR4 and its ligands CCL17 and CCL22 was significantly upregulated in AITL [86]. The application of spatial transcriptomics in this field is a novel and challenging technique. Studies have demonstrated that targeting CCR4 on Tregs and thereby downregulating Tregs recruitment can be used to treat AITL [87]. As mentioned earlier, CCR4 antagonists may be a clinical treatment for AITL, but many studies are needed to confirm this.
Adult T-cell Leukemia/Lymphoma (ATLL) is a peripheral T-lymphocyte tumor caused by human T-cellophilic virus type 1 (HTLV-1) [88]. Studies have shown that ATLL tumor cells highly express CCL17, CCL22, and CCR4 [34]. CCL17 and CCL22 create a favorable immunosuppressive TME by attracting CCR4+ Tregs into the TME. Multivariate analysis confirmed that high levels of CCL17 were an independent and significant poor prognostic factor in patients with ATLL, and that the overall survival of patients with ATLL who had high levels of CCL17 was significantly shorter than that of patients with low levels of CCL17. In contrast, serum CCL22 levels had no prognostic significance in ATLL patients [89]. One study performed whole transcriptome sequencing of ATLL patient samples, and CCR4 mutations were detected in 14/53 ATLL samples and consisted of nonsense or code-shift mutations. Mutated CCR4 isoforms promoted migration of ATLL cells to CCL17 and CCL22 and activation of PI3K/AKT in response to ligand binding [90]. This study suggests that somatic function acquired CCR4 mutations are implicated in the pathogenesis of ATLL and that inhibition of CCR4 signaling may have therapeutic potential in ATLL. This was also confirmed by a recent study in which CCR4 mutations expressed on ATLL cells enhanced the PI3K/AKT pathway upon binding of the chemokine CCL22 to CCR4 and promoted ATLL cell survival [57, 91]. Prawiro et al. found increased PLC activity and enhanced CCL22-induced chemotaxis of KK1 cells in an ATLL-derived cell line (KK1 cells) with the phospholipase C (PLC) γ1 S345F mutation. Reversal of its mutation resulted in decreased PLC activity, reduced proliferation, and aggregation of KK1 cells, and significantly reduced CCL22-induced chemotaxis of KK1 cells [92]. Tax protein is the product encoded by the tax gene in the HTLV-1 genome, and it has been demonstrated that Tax induces HTLV-1-infected T cells to produce the chemokine CCL22, which aids in the survival of HTLV-1-infected T cells by attracting Tregs to generate an immunosuppressive microenvironment [18].
Anaplastic large cell lymphoma (ALCL) is also a type of PTCL, and CCL17 was found to be expressed in most anaplastic lymphoma kinase (ALK)-negative ALCL, but not in ALK-positive ALCL. CCL17 was found to be [93]. CCL17 may serve as a diagnostic marker for ALK-negative ALCL patients [94].
3.2.5 Mantle cell lymphoma
Studies have shown that patients with mantle cell lymphoma (MCL) have elevated concentrations of the plasma chemokines CCL17 and CCL22 [95]. Excessive PI3K-δ activity has been reported to characterize MCL, and the PI3K-δ selective inhibitor CAL101 (GS-1101) inhibited the up-regulation of Akt phosphorylation and the production of chemokines CCL17 and CCL22 in the co-cultivation of MCL cells with stromal cells, suppressing the growth and survival of MCL cells [96]. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), was granted approval by the FDA in 2013 for the therapy of patients with MCL who had previously undergone at least one course of treatment with lenalidomide or other pharmaceutical agents. A phase 1 study of ibrutinib revealed a reduction in plasma chemokine CCL17 and CCL22 levels in patients with MCL who were treated with ibrutinib [97].
4 Expression and role of chemokines CCL17 and CCL22 and their receptor CCR4 in leukemia
4.1 Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a highly diverse disease with a variable prognosis. This is dependent on a number of factors, including immunophenotypes, cytogenetics and specific molecular markers, which in turn influence the most appropriate course of treatment [98]. A study revealed that the expression level of the CCL17 gene in the bone marrow of 189 patients with primary B-ALL was markedly elevated in comparison to the bone marrow of 43 healthy blood donors. Furthermore, the expression of CCL17 mRNA in patients with primary B-ALL was significantly higher than that observed in the complete remission group. In addition, CCL17 expression was higher in B-ALL cell lines (Sup-B15 cells and NALM-6 cells) in comparison to other acute myeloid leukemia (AML) cells and T-ALL cells [37]. This study suggests that aberrant expression of CCL17 in leukemia may be involved in the pathogenesis of B-ALL. Helios is a member of the Ikaros family of transcription factors, and the results of this study suggest that Helios may They play a crucial part in the regulation of differentiation, survival, and immune-suppressive functions of Tregs [99, 100]. It has been demonstrated that an elevated proportion of Helios+ Tregs in children with ALL promotes the development of ALL and the infiltration of ALL cells into the bone marrow, and may be involved in the regulation of bone marrow angiogenesis in ALL [101]. Subsequently, LI et al. showed that high expression of Helios in Tregs promotes the secretion of CCL22 by macrophages, dendritic cells, and ALL cells, which recruits more Tregs to the bone marrow and promotes immune escape of tumor cells [102].
4.2 Chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the developed world [103]. It has been found that serum concentrations of CCL17 and CCL22 are generally elevated in patients with CLL [104]. A multicenter prospective study demonstrated that plasma CCL17 was a valuable response marker at the end of treatment in pediatric CLL patients, but not in interim analyses after the first two cycles of chemotherapy. Further studies are needed to elucidate CCL17 as a marker of long-term progression-free survival [23].
Studies have confirmed that CLL cells produce the chemokines CCL17 and CCL22 [36]. CLL cells survive by receiving signals from the TME through a variety of receptors including BCRs, TLRs, and cytokine and chemokine receptors [104]. Interaction of CCL17 and CCR4 downstream of BCR and TLR promotes B-CLL cell survival and facilitates cell cycle progression [35]. IL21 is a major regulator of chemokine production in CLL cells, and studies have shown that IL21 down-regulates the expression of the chemokine genes CCL17 and CCL22 [105]. CD40L induces mRNA expression of CCL17 and CCL22 and stimulates CLL cells to produce the chemokines CCL17 and CCL22. CCL22 attracts CCR4+CD4+CD40L+ T cells, which further stimulate CLL cells to produce CCL17 and CCL22 [106]. NOTCH1 is a ligand-dependent transcription factor whose dysfunction is associated with tumor cell proliferation, differentiation and apoptosis in CLL [107]. Xu et al. showed that NOTCH1 c.7541-7542delCT (CTdel) mutation activates the expression of the downstream gene CCL17. The chemokine CCL17 causes migration of CD4+ T cells and promotes tumor cell survival, leading to increased aggressiveness of CLL and poor disease prognosis [107].
In 2014 the FDA approved ibrutinib for the treatment of CLL patients who had received at least one prior therapy. The study found that CLL patients experienced rapid improvement in symptoms and physical function after ibrutinib treatment was initiated, with plasma CCL17 levels continuing to decline, significantly at 4 weeks, for 12 months. Plasma CCL22 levels declined more slowly and remained down at 52 weeks [108].
4.3 Others
So far, CCR4 and its ligands CCL17 and CCL22 have been less studied in acute and chronic myeloid leukemia. Primary AML cells were cultured in vitro and expression of CCL17 and CCL22 was detected in most AML cells [109]. A recent scRNA-seq transcriptome analysis of mouse bone marrow showed that neutrophils do not express CCR4 and its ligands CCL17 and CCL22 [46].
5 Expression and role of chemokines CCL17 and CCL22 and their receptor CCR4 in multiple myeloma
Multiple myeloma (MM) is the second most common type of HM, and despite the introduction of IMiDs, proteasome inhibitors, and CD38 antibodies that have prolonged patient survival, MM is currently incurable [110]. Chemokine CCL17 levels have been reported to be significantly elevated in MM plasma [111]. In a phase II single-center open study of MM patients treated with oral Panobinostat in combination with lenalidomide and Dexamethasone, CCL22 was found to be reduced by 48%, 7%, and 72%, respectively, in all 3 patients who had a sustained response (> 4 months) to treatment. Thus, CCL22 may be a biomarker of sustained response to Panobinostat treatment in MM and warrants further investigation [111].
6 Others
Myelodysplastic syndromes (MDS) are bone marrow tumors with multiple genotypes and phenotypes [112]. It was found that CD8+ T-cell subsets in patients with low-risk MDS had reduced levels of CCR4 expression, which may consequently inhibit T-cell migration toward cells producing CCL17 and CCL22 [113]. So far, CCL17/CCL22-CCR4 has been less studied in MDS.
7 Targeting of CCR4
7.1 Mogamulizumab
Mogamulizumab is a fully humanized and glycosylated anti-CCR4 monoclonal antibody. Mogamulizumab exerts potent antitumor effects through Antibody-dependent cell-mediated cytotoxicity (ADCC), inducing cell-mediated cleavage of CCR4+ malignant T cells and CCR4+ Tregs. In 2012 mogamulizumab was approved in Japan for the treatment of CCR4-positive as well as refractory/recurrent ATLL. Mogamulizumab was approved for PTCL and CTCL in 2014[18].
7.1.1 Mogamulizumab for the treatment of ATLL
A multicenter phase II study evaluated the efficacy of mogamulizumab in patients with relapsed/refractory CCR4+ ATLL. Objective remission was observed in 13 of 26 evaluable patients (50%), including 8 CRs. Mogamulizumab administration resulted in a median progression-free survival (PFS) and median overall survival (OS) of 5.2 months and 13.7 months, respectively [114]. A subsequent multicentre phase II study demonstrated that patients with recurrent ATLL who were treated with mogamulizumab (n = 47) exhibited a higher objective response rate (ORR) and a superior progression-free survival (PFS) compared to those who received chemotherapy (n = 24) [115]. The results of the phase II studies indicate that mogamulizumab has the potential to be an effective salvage chemotherapy agent for patients with recurrent ATLL. A multicenter randomized phase II study demonstrated that the group that received mogamulizumab in conjunction with chemotherapy exhibited a higher CR rate than the group that did not utilize mogamulizumab monoclonal antibody in combination with intensive chemotherapy [116]. A post-marketing surveillance report from Japan evaluated the efficacy of mogamulizumab in 442 patients who received mogamulizumab as a single agent or in combination with a cytotoxic drug. The report showed that 177 of 308 patients treated with mogamulizumab as monotherapy achieved CR or partial response (PR), while 78 of 134 patients treated with the combination achieved CR or PR [117]. A recent retrospective study analyzed the clinical outcomes of 39 untreated aggressive ATLL transplant-ineligible patients. The overall survival rate at the four-year mark was 46.3% in the mogamulizumab first-line treatment group compared to 20.6% in the chemotherapy-only group. Additionally, this survival benefit was observed in elderly individuals. This study proposes that a first-line mogamulizumab-based treatment may represent a promising strategy for individuals with ATLL who are not eligible for transplantation, particularly the elderly [118].
Allogeneic hematopoietic stem cell transplantation (Allo-SCT) is considered a therapeutic intervention for individuals diagnosed with ATLL, and mogamulizumab has been studied in patients with ATLL receiving allo-SCT. A retrospective study was conducted involving 130 recipients of allo-SCT who were diagnosed with aggressive ATLL. The study demonstrated a higher occurrence of grade 3 to 4 acute GVHD at day 100 and lower 1-year OS compared with patients who did not receive pre-transplant mogamulizumab therapy [119]. Another retrospective study analyzed 996 allo-SCT recipients with newly diagnosed ATLL who received intensive chemotherapy as first-line treatment. Patients receiving pre-transplant administration of mogamulizumab demonstrated an elevated risk of grade 3 to 4 acute GVHD (n = 82) and higher non-relapse mortality (NRM) at 1 year, compared to patients who were not administered mogamulizumab. In addition, patients given mogamulizumab prior to transplantation had significantly lower OS rates than patients not given mogamulizumab [120]. A large national retrospective study enrolled 723 patients with recurrent ATLL. 132 patients received allo-SCT, of whom 25 received mogamulizumab pre-transplant administration. The NRM at 1 year after allo-SCT was higher in patients treated with mogamulizumab before allo-SCT than in patients not treated with mogamulizumab [121]. These findings suggest that mogamulizumab is best avoided in newly diagnosed ATLL patients amenable to allo-SCT who are concerned about the development of GVHD and NRM.
7.1.2 Adverse effects resulting from using mogamulizumab.
In a recent study assessing the safety and effectiveness of mogamulizumab, 1,290 patients with solid tumors, PTCL, CTCL, and ATLL were enrolled. After starting mogamulizumab therapy, approximately 43% of patients had a full or partial remission, and skin rash, lymphopenia, and neutropenia were the most frequent adverse events (≥ grade 3) [122]. Additional documented severe side effects linked to mogamulizumab therapy comprise cerebral EBV+ DLBCL, cytomegalovirus (CMV) infection, and hepatitis B virus (HBV) reactivation [123, 124]. These side effects could be brought on by the leukopenia and lymphopenia that mogamulizumab causes [122]. The most frequent treatment-emergent adverse events (TEAE) in mogamulizumab-treated patients were infusion-related reactions (33 percent) and drug rash (24 percent), according to a study on long-term disease control and safety in patients with CTCL treated with the medication. While the patients who received mogamulizumab treatment for the longest duration showed acceptable disease control, they also had a higher incidence of TEAE than the overall safe population. This implies that patients were able to continue their treatment and that TEAE was generally manageable [125]. According to a recent study, vitiligo may be brought on by mogamulizumab in patients with Sézary syndrome, and the onset of vitiligo may be a good indicator of how well a treatment is working [126]. The risk of graft-versus-host disease (GVHD) may increase if allo-HSCT is carried out following mogamulizumab therapy [127]. Moreover, individuals receiving mogamulizumab treatment have a markedly increased risk of developing severe intestinal GVHD and CMV enterocolitis, both of which can be fatal. The risk of GVHD can be predicted by measuring the amount of Tregs or the concentration of mogamulizumab at allo-HSCT [128].
In summary, mogamulizumab showed effectiveness in the treatment of HM including ATLL, PTCL and CTCL, but its adverse effects need to be further studied.
7.2 Small molecule CCR4 antagonists
FLX475 is a small molecule CCR4 antagonist that inhibits the migration of Tregs into tumors. Antitumor activity, including complete remission and combination activity in response to FLX475 monotherapy, was observed in phase 1/2 trials of oral FLX475 as monotherapy and in combination with pembrolizumab with an acceptable safety profile [129]. CCR4-351, a highly specific CCR4 antagonist. In vitro experimental studies revealed that Raji cells produce (human Burkitt's lymphoma cells) chemokines CCL17 and CCL22, and that CCR4-351 inhibits the migration of CCRF-CEM CD4+ T-lymphoblasts into Raji cell supernatants. In vivo migration modeling confirmed that CCR4-351 inhibited the migratory association between CCR4+ Treg and CCL17/CCL22-producing EBV+ Raji cells [28]. An in vitro and in vivo model using CCR4-351 was established to evaluate the migration and antitumor effects of Tregs, and the results showed that the migration of CCR4+ Tregs in tumors drove tumor progression and resistance to treatment with checkpoint inhibitors (CPIs). In a tumor model with high baseline levels of CCR4 ligand, blocking CCR4 reduced the number of Tregs and enhanced anti-tumor immune activity. In tumor models with low baseline levels of CCR4 ligand, treatment with immune CPIs resulted in a significant increase in the number of CCR4 ligands and Tregs. Inhibition of CCR4 reduced the frequency of Tregs and enhanced the antitumor effects of CPIs [87]. This study provides a clinical rationale for the combined use of CCR4 antagonists with CPIs in the treatment of tumors. Compound 22 is a CCR4 inhibitor. Studies have confirmed that compound 22 ameliorates atopic dermatitis (AD)-like skin lesions by reducing skin lesions and inhibiting the proliferation of Th2 and Th17 cells in localized lymph nodes [130]. C021 is a specific inhibitor of CCR4. CCR4 plays a key role in enhancing hematoma clearance after cerebral hemorrhage. Animal experiments confirmed that C021 reversed the neuroprotective effect of rCCL17 [131].
8 Conclusions
In summary, CCL17 and CCL22 and their receptor CCR4 play important roles in hematologic tumors, and their expression and mechanism of action are closely related to the occurrence, development, and prognosis of hematologic tumors. By reviewing their expression, mechanism of action, and clinical significance in hematologic tumors, we can see that CCL17 and CCL22 and their receptor CCR4 have become a new research hotspot and therapeutic target in the diagnosis and treatment of hematologic tumors. Indeed, therapies targeting CCL17 and CCL22 and their receptor CCR4 are constantly being developed and refined. It is foreseeable that the future diagnosis and treatment will be more dominated by gene therapy and targeted therapy and will no longer be limited to traditional means such as chemotherapy and radiotherapy. We believe that in future studies, CCL17 and CCL22 and their receptor CCR4 will be further applied in clinical treatment, providing more effective means and directions for the treatment of hematological tumors.
Data availability
No datasets were generated or analysed during the current study.
Code availability
Not applicable.
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Shasha Zou: Writing—original draft, Writing—review & editing, Conceptualization. Yonghuai Feng: Supervision, Project administration, Funding acquisition. Bo Liu: Supervision, revision, Project administration.
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Zou, S., Liu, B. & Feng, Y. CCL17, CCL22 and their receptor CCR4 in hematologic malignancies. Discov Onc 15, 412 (2024). https://doi.org/10.1007/s12672-024-01210-x
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DOI: https://doi.org/10.1007/s12672-024-01210-x