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Shedding light on macrophage immunotherapy in lung cancer

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Abstract

The search for therapeutic options for lung cancer continues to advance, with rapid advances in the search for therapies to improve patient prognosis. At present, systemic chemotherapy, immune checkpoint inhibitor therapy, antiangiogenic therapy, and targeted therapy for driver gene positivity are available in the clinic. Common clinical treatments fail to achieve desired outcomes due to immunosuppression of the tumor microenvironment (TME). Tumor immune evasion is mediated by cytokines, chemokines, immune cells, and other cells such as vascular endothelial cells within the tumor immune microenvironment. Tumor-associated macrophages (TAMs) are important immune cells in the TME, inducing tumor angiogenesis, encouraging tumor cell proliferation and migration, and suppressing antitumor immune responses. Thus, TAM targeting becomes the key to lung cancer immunotherapy. This review focuses on macrophage phenotype, polarization mechanism, role in lung cancer, and advances in macrophage centric immunotherapies.

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Abbreviations

TME:

Tumor microenvironment

NSCLC:

Non-small cell lung cancer

ROS:

Reactive oxygen species

TGF-β:

Transforming growth factor beta

VEGF:

Vascular endothelial growth factor

PD-1:

Programmed cell death protein

PD-L1:

Programmed death ligand 1

CSF-1:

Colony-stimulating factor 1

CLL:

Chronic lymphocytic leukemia

EMT:

Epithelial–mesenchymal transition

ICB:

Immune checkpoint blockade

TAMs:

Tumor-associated macrophages

TDF:

Tumor-derived factor

LPS:

Lipopolysaccharide

References

  • Anfray C, Ummarino A, Andon FT, Allavena P (2019) Current strategies to target tumor-associated-macrophages to improve anti-tumor immune responses. Cells 9(1):46

    PubMed  PubMed Central  Google Scholar 

  • Baghdadi M, Wada H, Nakanishi S, Abe H, Han N, Putra WE et al (2016) Chemotherapy-induced IL34 enhances immunosuppression by tumor-associated macrophages and mediates survival of chemoresistant lung cancer cells. Cancer Res 76(20):6030–6042

    CAS  PubMed  Google Scholar 

  • Barclay AN, Van den Berg TK (2014) The interaction between signal regulatory protein alpha (SIRPalpha) and CD47: structure, function, and therapeutic target. Annu Rev Immunol 32:25–50

    CAS  PubMed  Google Scholar 

  • Bonde AK, Tischler V, Kumar S, Soltermann A, Schwendener RA (2012) Intratumoral macrophages contribute to epithelial–mesenchymal transition in solid tumors. BMC Cancer 12:35

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bremnes RM, Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R et al (2011) The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol 6(1):209–217

    PubMed  Google Scholar 

  • Cai H, Zhang Y, Wang J, Gu J (2021) Defects in macrophage reprogramming in cancer therapy: the negative impact of PD-L1/PD-1. Front Immunol 12:690869

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Zhang K, Zhi Y, Wu Y, Chen B, Bai J et al (2021) Tumor-derived exosomal miR-19b-3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via Hippo pathway. Clin Transl Med 11(9):e478

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng C, Hu Z, Cao L, Peng C, He Y (2019) The scavenger receptor SCARA1 (CD204) recognizes dead cells through spectrin. J Biol Chem 294(49):18881–18897

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cotechini T, Atallah A, Grossman A (2021) Tissue-resident and recruited macrophages in primary tumor and metastatic microenvironments: potential targets in cancer therapy. Cells 10(4):960

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cruz-Bermudez A, Laza-Briviesca R, Vicente-Blanco RJ, Garcia-Grande A, Coronado MJ, Laine-Menendez S et al (2019) Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-beta signaling. Free Radic Biol Med 130:163–173

    CAS  PubMed  Google Scholar 

  • Dai X, Lu L, Deng S, Meng J, Wan C, Huang J et al (2020) USP7 targeting modulates anti-tumor immune response by reprogramming tumor-associated macrophages in lung cancer. Theranostics 10(20):9332–9347

    CAS  PubMed  PubMed Central  Google Scholar 

  • da Silva MC, Breckwoldt MO, Vinchi F, Correia MP, Stojanovic A, Thielmann CM et al (2017) Iron induces anti-tumor activity in tumor-associated macrophages. Front Immunol 8:1479

    Google Scholar 

  • DeNardo DG, Ruffell B (2019) Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol 19(6):369–382

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng P, Zhou R, Zhang J, Cao L (2021) Increased expression of KNSTRN in lung adenocarcinoma predicts poor prognosis: a bioinformatics analysis based on TCGA data. J Cancer 12(11):3239–3248

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng L, Jian Z, Xu T, Li F, Deng H, Zhou Y et al (2023) Macrophage polarization: an important candidate regulator for lung diseases. Molecules 28(5):2379

    CAS  PubMed  PubMed Central  Google Scholar 

  • Devalaraja S, To TKJ, Folkert IW, Natesan R, Alam MZ, Li M et al (2020) Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression. Cell 180(6):1098–114.e16

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dhawan D, Ramos-Vara JA, Naughton JF, Cheng L, Low PS, Rothenbuhler R et al (2013) Targeting folate receptors to treat invasive urinary bladder cancer. Cancer Res 73(2):875–884

    CAS  PubMed  Google Scholar 

  • Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG et al (2010) Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 70(19):7465–7475

    CAS  PubMed  PubMed Central  Google Scholar 

  • Duan Z, Luo Y (2021) Targeting macrophages in cancer immunotherapy. Signal Transduct Target Ther 6(1):127

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fenalti G, Villanueva N, Griffith M, Pagarigan B, Lakkaraju SK, Huang RY et al (2021) Structure of the human marker of self 5-transmembrane receptor CD47. Nat Commun 12(1):5218

    CAS  PubMed  PubMed Central  Google Scholar 

  • Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13(5):1472–1479

    CAS  PubMed  Google Scholar 

  • Gudgeon J, Marin-Rubio JL, Trost M (2022) The role of macrophage scavenger receptor 1 (MSR1) in inflammatory disorders and cancer. Front Immunol 13:1012002

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gurtner A, Manni I, Piaggio G (2017) NF-Y in cancer: impact on cell transformation of a gene essential for proliferation. Biochim Biophys Acta Gene Regul Mech 1860(5):604–616

    CAS  PubMed  Google Scholar 

  • Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian BZ et al (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5(9):932–943

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL et al (2017) Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin Cancer Res 23(1):137–148

    CAS  PubMed  Google Scholar 

  • Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A et al (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3(95):9573

    Google Scholar 

  • Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11(5):373–384

    CAS  PubMed  Google Scholar 

  • Kelley JL, Ozment TR, Li C, Schweitzer JB, Williams DL (2014) Scavenger receptor-A (CD204): a two-edged sword in health and disease. Crit Rev Immunol 34(3):241–261

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koukourakis MI, Kalamida D, Mitrakas AG, Liousia M, Pouliliou S, Sivridis E et al (2017) Metabolic cooperation between co-cultured lung cancer cells and lung fibroblasts. Lab Investig J Tech Methods Pathol 97(11):1321–1331

    CAS  Google Scholar 

  • Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T et al (2013) Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat 12(3):259–267

    CAS  PubMed  Google Scholar 

  • Li Y, Cao F, Li M, Li P, Yu Y, Xiang L et al (2018) Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages. J Exp Clin Cancer Res 37(1):259

    PubMed  PubMed Central  Google Scholar 

  • Li M, Li M, Yang Y, Liu Y, Xie H, Yu Q et al (2020) Remodeling tumor immune microenvironment via targeted blockade of PI3K-gamma and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy. J Control Release 321:23–35

    CAS  PubMed  Google Scholar 

  • Liu J, Xavy S, Mihardja S, Chen S, Sompalli K, Feng D et al (2020) Targeting macrophage checkpoint inhibitor SIRPalpha for anticancer therapy. JCI Insight. https://doi.org/10.1172/jci.insight.134728

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C et al (2019) Current progress in CAR-T Cell therapy for solid tumors. Int J Biol Sci 15(12):2548–2560

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma YF, Chen Y, Fang D, Huang Q, Luo Z, Qin Q et al (2021) The immune-related gene CD52 is a favorable biomarker for breast cancer prognosis. Gland Surg 10(2):780–798

    PubMed  PubMed Central  Google Scholar 

  • Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212(4):435–445

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nazareth MR, Broderick L, Simpson-Abelson MR, Kelleher RJ Jr, Yokota SJ, Bankert RB (2007) Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J Immunol 178(9):5552–5562

    CAS  PubMed  Google Scholar 

  • Ngambenjawong C, Gustafson HH, Pun SH (2017) Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv Drug Deliv Rev 114:206–221

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ovais M, Guo M, Chen C (2019) Tailoring nanomaterials for targeting tumor-associated macrophages. Adv Mater 31(19):e1808303

    PubMed  Google Scholar 

  • Ramesh A, Kumar S, Brouillard A, Nandi D, Kulkarni A (2020) A Nitric Oxide (NO) nanoreporter for noninvasive real-time imaging of macrophage immunotherapy. Adv Mater 32(24):e2000648

    PubMed  Google Scholar 

  • Ravi J, Elbaz M, Wani NA, Nasser MW, Ganju RK (2016) Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway. Mol Carcinog 55(12):2063–2076

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reyes NJ, O’Koren EG, Saban DR (2017) New insights into mononuclear phagocyte biology from the visual system. Nat Rev Immunol 17(5):322–332

    CAS  PubMed  PubMed Central  Google Scholar 

  • Richards DM, Hettinger J, Feuerer M (2013) Monocytes and macrophages in cancer: development and functions. Cancer Microenviron 6(2):179–191

    CAS  PubMed  Google Scholar 

  • Rigo A, Gottardi M, Zamo A, Mauri P, Bonifacio M, Krampera M et al (2010) Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12. Mol Cancer 9:273

    PubMed  PubMed Central  Google Scholar 

  • Ruffell B, Coussens LM (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27(4):462–472

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA (2008) Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer 15(4):1069–1074

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez-Martin L, Estecha A, Samaniego R, Sanchez-Ramon S, Vega MA, Sanchez-Mateos P (2011) The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117(1):88–97

    CAS  PubMed  Google Scholar 

  • Sarode P, Schaefer MB, Grimminger F, Seeger W, Savai R (2020) Macrophage and tumor cell cross-talk is fundamental for lung tumor progression: we need to talk. Front Oncol 10:324

    PubMed  PubMed Central  Google Scholar 

  • Sawa-Wejksza K, Kandefer-Szerszen M (2018) Tumor-associated macrophages as target for antitumor therapy. Arch Immunol Ther Exp (warsz) 66(2):97–111

    CAS  PubMed  Google Scholar 

  • Schultze JL, Schmieder A, Goerdt S (2015) Macrophage activation in human diseases. Semin Immunol 27(4):249–256

    CAS  PubMed  Google Scholar 

  • Shi Y, Lammers T (2019) Combining nanomedicine and immunotherapy. Acc Chem Res 52(6):1543–1554

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 267(2):204–215

    CAS  PubMed  Google Scholar 

  • Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T et al (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362(10):875–885

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sterner RC, Sterner RM (2021) CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J 11(4):69

    PubMed  PubMed Central  Google Scholar 

  • Stifano G, Christmann RB (2016) Macrophage involvement in systemic sclerosis: do we need more evidence? Curr Rheumatol Rep 18(1):2

    PubMed  Google Scholar 

  • Takahashi R, Ijichi H, Sano M, Miyabayashi K, Mohri D, Kim J et al (2020) Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer. Sci Rep 10(1):21194

    CAS  PubMed  PubMed Central  Google Scholar 

  • Timaner M, Bril R, Kaidar-Person O, Rachman-Tzemah C, Alishekevitz D, Kotsofruk R et al (2015) Dequalinium blocks macrophage-induced metastasis following local radiation. Oncotarget 6(29):27537–27554

    PubMed  PubMed Central  Google Scholar 

  • Trauelsen M, Hiron TK, Lin D, Petersen JE, Breton B, Husted AS et al (2021) Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling. Cell Rep 35(11):109246

    CAS  PubMed  Google Scholar 

  • Tsai RK, Discher DE (2008) Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J Cell Biol 180(5):989–1003

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vernon-Wilson EF, Kee WJ, Willis AC, Barclay AN, Simmons DL, Brown MH (2000) CD47 is a ligand for rat macrophage membrane signal regulatory protein SIRP (OX41) and human SIRPalpha 1. Eur J Immunol 30(8):2130–2137

    CAS  PubMed  Google Scholar 

  • Wang N, Liang H, Zen K (2014) Molecular mechanisms that influence the macrophage m1–m2 polarization balance. Front Immunol 5:614

    PubMed  PubMed Central  Google Scholar 

  • Wang J, Li D, Cang H, Guo B (2019) Crosstalk between cancer and immune cells: role of tumor-associated macrophages in the tumor microenvironment. Cancer Med 8(10):4709–4721

    PubMed  PubMed Central  Google Scholar 

  • Weichand B, Popp R, Dziumbla S, Mora J, Strack E, Elwakeel E et al (2017) S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1beta. J Exp Med 214(9):2695–2713

    CAS  PubMed  PubMed Central  Google Scholar 

  • Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23(35):8959–8967

    PubMed  Google Scholar 

  • Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL et al (2020) Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell 77(2):213–27.e5

    CAS  PubMed  Google Scholar 

  • Xiao H, Guo Y, Li B, Li X, Wang Y, Han S et al (2020) M2-Like tumor-associated macrophage-targeted codelivery of STAT6 inhibitor and IKKbeta siRNA induces M2-to-M1 repolarization for cancer immunotherapy with low immune side effects. ACS Cent Sci 6(7):1208–1222

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu J, Escamilla J, Mok S, David J, Priceman S, West B et al (2013) CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res 73(9):2782–2794

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Shao R, Huang H, Wang X, Rong Z, Lin Y (2019) Engineering macrophages to phagocytose cancer cells by blocking the CD47/SIRPa axis. Cancer Med 8(9):4245–4253

    PubMed  PubMed Central  Google Scholar 

  • Zhao H, Song S, Ma J, Yan Z, Xie H, Feng Y et al (2022) CD47 as a promising therapeutic target in oncology. Front Immunol 13:757480

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Luan J, Huang C, Li J (2021) Tumor-associated macrophages in hepatocellular carcinoma: friend or foe? Gut Liver 15(4):500–516

    CAS  PubMed  Google Scholar 

  • Zhu L, Jones C, Zhang G (2018) The role of phospholipase C signaling in macrophage-mediated inflammatory response. J Immunol Res 2018:5201759

    PubMed  PubMed Central  Google Scholar 

  • Zhu Y, Li X, Wang L, Hong X, Yang J (2022) Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment. Front Endocrinol (lausanne) 13:988295

    PubMed  PubMed Central  Google Scholar 

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This work has been funded with support from Nantong Science and Technology Bureau.

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QX and YLZ provided the direction and guidance of this manuscript. HM and ZZ wrote the whole manuscript. QH, HC, and GW made significant revisions to the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Youlang Zhou or Qun Xue.

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Ma, H., Zhang, Z., Hu, Q. et al. Shedding light on macrophage immunotherapy in lung cancer. J Cancer Res Clin Oncol 149, 8143–8152 (2023). https://doi.org/10.1007/s00432-023-04740-z

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