肿瘤相关巨噬细胞在非小细胞肺癌中的研究进展
Research Progress of Tumor Associated Macrophages in Non-Small Cell Lung Cancer
DOI: 10.12677/ACM.2023.134827, PDF,   
作者: 彭修法:青岛大学医学部,山东 青岛;张春玲*:青岛大学第二附属医院呼吸与危重症医学科,山东 青岛
关键词: 肿瘤相关巨噬细胞极化非小细胞肺癌Tumor-Associated Macrophages Polarization Non-Small Cell Lung Cancer
摘要: 作为一种恶性肿瘤,肺癌是癌症相关死亡最常见原因。其主要分小细胞肺癌(small cell lung cancer, SCLC)与非小细胞肺癌(non-small cell lung cancer, NSCLC)两种类型,其中最常见亚型为NSCLC。随着对肿瘤认识的加深,新的治疗手段不仅集中于靶向肿瘤细胞本身,还逐渐认识到破坏肿瘤和其所在微环境中间质细胞之间相互作用的重要性。肿瘤相关巨噬细胞(Tumor-associated macrophages, TAMs)广泛存在于不同肿瘤的肿瘤微环境(tumor microenvironment, TME),是TME中占比最高的细胞成分。证据表明TAMs与NSCLC的发生、发展有密切的联系。因此靶向TAMs有可能成为肺癌治疗的潜在靶点。本文从肿瘤相关巨噬细胞的来源、极化、与肿瘤细胞的相互作用以及靶向肿瘤相关巨噬细胞等多个方面的研究进展进行综述。
Abstract: As a malignant tumor, lung cancer is the most common cause of cancer-related death, which is mainly divided into non-small cell lung cancer (NSCLC), the most common subtype and small cell lung cancer (SCLC). With the deepening understanding of tumor, besides targeting tumor cells, re-searchers gradually realize the significance of destroying the interaction between tumor and its microenvironment intermediate cells. Tumor associated macrophages (TAMs) widely exist in tumor microenvironment (TME), and are the most vital cell component in TME. Evidence shows that TAMs are closely related to the occurrence and development of NSCLC. Therefore, TAMs may become a potential target for the treatment of lung cancer. In this paper, we reviewed the progress of TAMs in the aspects of origin, polarization, interaction with NSCLC tumor cells and targeting TAMs.
文章引用:彭修法, 张春玲. 肿瘤相关巨噬细胞在非小细胞肺癌中的研究进展[J]. 临床医学进展, 2023, 13(4): 5855-5863. https://doi.org/10.12677/ACM.2023.134827

参考文献

[1] Sung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. [Google Scholar] [CrossRef] [PubMed]
[2] Liu, X.H., Liu, Z.L., Sun, M., et al. (2013) The Long Non-Coding RNA HOTAIR Indicates a Poor Prognosis and Promotes Metastasis in Non-Small Cell Lung Cancer. BMC Cancer, 13, Article No. 464. [Google Scholar] [CrossRef] [PubMed]
[3] Aberle, D.R., Adams, A.M., Berg, C.D., et al. (2011) Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. The New England Journal of Medicine, 365, 395-409. [Google Scholar] [CrossRef
[4] Lee, S.H., Suh, I.B., Lee, E.J., et al. (2013) Relationships of Coagulation Factor XIII Activity with Cell-Type and Stage of Non-Small Cell Lung Cancer. Yonsei Medical Journal, 54, 1394-1399. [Google Scholar] [CrossRef] [PubMed]
[5] Song, G., Qin, T., Liu, H., et al. (2010) Quantitative Breath Analysis of Volatile Organic Compounds of Lung Cancer Patients. Lung Cancer (Amsterdam, Netherlands), 67, 227-231. [Google Scholar] [CrossRef] [PubMed]
[6] Sedighzadeh, S.S., Khoshbin, A.P., Razi, S., et al. (2021) A Narrative Review of Tumor-Associated Macrophages in Lung Cancer: Regulation of Macrophage Polarization and Therapeutic Implications. Translational Lung Cancer Research, 10, 1889-1916. [Google Scholar] [CrossRef] [PubMed]
[7] Cortez-Retamozo, V., Etzrodt, M., Newton, A., et al. (2012) Origins of Tumor-Associated Macrophages and Neutrophils. Proceedings of the National Academy of Sciences of the United States of America, 109, 2491-2496. [Google Scholar] [CrossRef] [PubMed]
[8] Shand, F.H.W., Ueha, S., Otsuji, M., et al. (2014) Tracking of inter-tissue migration reveals the origins of tumor-infiltrating monocytes. Proceedings of the National Academy of Sciences of the United States of America, 111, 7771-7776. [Google Scholar] [CrossRef] [PubMed]
[9] Lewis, C.E., Harney, A.S. and Pollard, J.W. (2016) The Multifaceted Role of Perivascular Macrophages in Tumors. Cancer Cell, 30, 365. [Google Scholar] [CrossRef] [PubMed]
[10] Kowal, J., Kornete, M. and Joyce, J.A. (2019) Re-Education of Macrophages as a Therapeutic Strategy in Cancer. Immunotherapy, 11, 677-689. [Google Scholar] [CrossRef] [PubMed]
[11] Mills, C.D., Kincaid, K., Alt, J.M., et al. (2017) Pillars Article: M-1/M-2 Macrophages and the Th1/Th2 Paradigm. J. Immunol. 2000. 164: 6166-6173. Journal of Immunology (Balti-more, Md: 1950), 199, 2194-2201.
[12] Biswas, S.K. and Mantovani, A. (2010) Macrophage Plasticity and Interaction with Lymphocyte Subsets: Cancer as a Paradigm. Nature Immunology, 11, 889-896. [Google Scholar] [CrossRef] [PubMed]
[13] Duthie, M.S. and Reed, S.G. (2021) Skin Tests for the Detection of Mycobac-terial Infections: Achievements, Current Perspectives, and Implications for Other Diseases. Applied Microbiology and Bi-otechnology, 105, 503-508. [Google Scholar] [CrossRef] [PubMed]
[14] Fleetwood, A.J., Lawrence, T., Hamilton, J.A., et al. (2007) Granulocyte-Macrophage Colony-Stimulating Factor (CSF) and Macrophage CSF-Dependent Macrophage Phenotypes Display Differences in Cytokine Profiles and Transcription Factor Activities: Implications for CSF Blockade in Inflam-mation. Journal of Immunology (Baltimore, Md: 1950), 178, 5245-5252. [Google Scholar] [CrossRef] [PubMed]
[15] Fujiwara, N. and Kobayashi, K. (2005) Macrophages in Inflam-mation. Current Drug Targets Inflammation and Allergy, 4, 281-286. [Google Scholar] [CrossRef] [PubMed]
[16] Porta, C., Riboldi, E., Ippolito, A., et al. (2015) Molecular and Epigenetic Basis of Macrophage Polarized Activation. Seminars in Immunology, 27, 237-248. [Google Scholar] [CrossRef] [PubMed]
[17] Schultze, J.L. and Schmidt, S.V. (2015) Molecular Features of Macrophage Activation. Seminars in Immunology, 27, 416-423. [Google Scholar] [CrossRef] [PubMed]
[18] Lewis, C.E. and Pollard, J.W. (2006) Distinct Role of Macro-phages in Different Tumor Microenvironments. Cancer Research, 66, 605-612. [Google Scholar] [CrossRef
[19] De Sousa, J.R., Martins De Sousa, R.P., De Souza Aarao, T.L., et al. (2016) In Situ Expression of M2 Macrophage Subpopulation in Leprosy Skin Lesions. Acta Tropica, 157, 108-114. [Google Scholar] [CrossRef] [PubMed]
[20] Griess, B., Mir, S., Datta, K., et al. (2020) Scav-enging Reactive Oxygen Species Selectively Inhibits M2 Macrophage Polarization and Their Pro-Tumorigenic Function in Part, via Stat3 Suppression. Free Radical Biology & Medicine, 147, 48-60. [Google Scholar] [CrossRef] [PubMed]
[21] Jayasingam, S.D., Citartan, M., Thang, T.H., et al. (2019) Evaluating the Polarization of Tumor-Associated Macrophages into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice. Frontiers in Oncology, 9, 1512. [Google Scholar] [CrossRef] [PubMed]
[22] Zhang, Q., Huang, F., Yaom Y., et al. (2019) Interaction of Trans-forming Growth Factor-β-Smads/microRNA-362-3p/ CD82 Mediated by M2 Macrophages Promotes the Process of Ep-ithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells. Cancer Science, 110, 2507-2519. [Google Scholar] [CrossRef] [PubMed]
[23] Denardo, D.G. and Ruffell, B. (2019) Macrophages as Regulators of Tu-mour Immunity and Immunotherapy. Nature Reviews Immunology, 19, 369-382. [Google Scholar] [CrossRef] [PubMed]
[24] Zhang, M., He, Y., Sun, X., et al. (2014) A High M1/M2 Ratio of Tumor-Associated Macrophages Is Associated with Extended Survival in Ovarian Cancer Patients. Journal of Ovarian Research, 7, Article No. 19. [Google Scholar] [CrossRef] [PubMed]
[25] Takeuchi, H., Tanaka, M., Tanaka, A., et al. (2016) Predominance of M2-Polarized Macrophages in Bladder Cancer Affects Angiogenesis, Tumor Grade and Invasiveness. Oncology Letters, 11, 3403-3408. [Google Scholar] [CrossRef] [PubMed]
[26] Singhal, S., Stadanlick, J., Annunziata, M.J., et al. (2019) Human Tu-mor-Associated Monocytes/Macrophages and Their Regulation of T Cell Responses in Early-Stage Lung Cancer. Science Translational Medicine, 11, eaat1500, [Google Scholar] [CrossRef] [PubMed]
[27] Chong, B.F., Tseng, L.C., Hosler, G.A., et al. (2015) A Subset of CD163+ Macrophages Displays Mixed Polarizations in Discoid Lupus Skin. Arthritis Research & Therapy, 17, Arti-cle No. 324. [Google Scholar] [CrossRef] [PubMed]
[28] Elliott, L.A., Doherty, G.A., Sheahan, K., et al. (2017) Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity. Frontiers in Immunology, 8, Article No. 86. [Google Scholar] [CrossRef] [PubMed]
[29] Zhang, Q.W., Liu, L., Gong, C.Y., et al. (2012) Prognostic Significance of Tumor-Associated Macrophages in Solid Tumor: A Meta-Analysis of the Literature. PLOS ONE, 7, e50946. [Google Scholar] [CrossRef] [PubMed]
[30] Dai, F., Liu, L., Che, G., et al. (2010) The Number and Microlocalization of Tumor-Associated Immune Cells Are Associated with Patient’s Survival Time in Non-Small Cell Lung Cancer. BMC Cancer, 10, Article No. 220. [Google Scholar] [CrossRef] [PubMed]
[31] Lin, E.Y., Li, J.F., Gnatovskiy, L., et al. (2006) Macrophages Reg-ulate the Angiogenic Switch in a Mouse Model of Breast Cancer. Cancer Research, 66, 11238-11246. [Google Scholar] [CrossRef
[32] Sierra, J.R., Corso, S., Caione, L., et al. (2008) Tumor An-giogenesis and Progression Are Enhanced by Sema4D Produced by Tumor-Associated Macrophages. The Journal of Experimental Medicine, 205, 1673-1685. [Google Scholar] [CrossRef] [PubMed]
[33] Lin, L., Chen, Y.S., Yao, Y.D., et al. (2015) CCL18 from Tu-mor-Associated Macrophages Promotes Angiogenesis in Breast Cancer. Oncotarget, 6, 34758-34773. [Google Scholar] [CrossRef] [PubMed]
[34] Rolny, C,, Mazzone, M., Tugues, S., et al. (2011) HRG Inhibits Tumor Growth and Metastasis by Inducing Macrophage Polarization and Vessel Normalization through Downregulation of PlGF. Cancer Cell, 19, 31-44. [Google Scholar] [CrossRef] [PubMed]
[35] Chen, P., Huang, Y., Bong, R., et al. (2011) Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17, 7230-7239. [Google Scholar] [CrossRef
[36] Guruvayoorappan, C. (2008) Tumor versus Tu-mor-Associated Macrophages: How Hot Is the Link? Integrative Cancer Therapies, 7, 90-95. [Google Scholar] [CrossRef] [PubMed]
[37] Deryugina, E.I., Zajac, E., Juncker-Jensen, A., et al. (2014) Tis-sue-Infiltrating Neutrophils Constitute the Major in Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Micro-environment. Neoplasia (New York, NY), 16, 771-788. [Google Scholar] [CrossRef] [PubMed]
[38] Lewis, C.E., Harney, A.S. and Pollard, J.W. (2016) The Multifac-eted Role of Perivascular Macrophages in Tumors. Cancer Cell, 30, 18-25. [Google Scholar] [CrossRef] [PubMed]
[39] Schoppmann, S.F., Birner, P., Stöckl, J., et al. (2002) Tu-mor-Associated Macrophages Express Lymphatic Endothelial Growth Factors and Are Related to Peritumoral Lymphan-giogenesis. The American Journal of Pathology, 161, 947-956. [Google Scholar] [CrossRef
[40] Ji, R.C. (2012) Macrophages Are Important Mediators of ei-ther Tumor- or Inflammation-Induced Lymphangiogenesis. Cellular and Molecular Life Sciences: CMLS, 69, 897-914. [Google Scholar] [CrossRef] [PubMed]
[41] Jung, M., Ören, B., Mora, J., et al. (2016) Lipocalin 2 from Mac-rophages Stimulated by Tumor Cell-Derived Sphingosine 1-Phosphate Promotes Lymphangiogenesis and Tumor Metas-tasis. Science Signaling, 9, ra64. [Google Scholar] [CrossRef] [PubMed]
[42] Cannarile, M.A., Weisser, M., Jacob, W., et al. (2017) Colo-ny-Stimulating Factor 1 Receptor (CSF1R) Inhibitors in Cancer Therapy. Journal for Immunotherapy of Cancer, 5, 53. [Google Scholar] [CrossRef] [PubMed]
[43] Jeong, H., Kim, S., Hong, B.J., et al. (2019) Tumor-Associated Macrophages Enhance Tumor Hypoxia and Aerobic Glycolysis. Cancer Research, 79, 795-806. [Google Scholar] [CrossRef
[44] Jeong, S.K., Kim, J.S., Lee, C.G., et al. (2017) Tumor As-sociated Macrophages Provide the Survival Resistance of Tumor Cells to Hypoxic Microenvironmental Condition through IL-6 Receptor-Mediated Signals. Immunobiology, 222, 55-65. [Google Scholar] [CrossRef] [PubMed]
[45] Moisan, F., Francisco, E.B., Brozovic, A., et al. (2014) En-hancement of Paclitaxel and Carboplatin Therapies by CCL2 Blockade in Ovarian Cancers. Molecular Oncology, 8, 1231-1239. [Google Scholar] [CrossRef] [PubMed]
[46] Wang, R., Zhang, J., Chen, S., et al. (2011) Tu-mor-Associated Macrophages Provide a Suitable Microenvironment for Non-Small Lung Cancer Invasion and Progres-sion. Lung Cancer (Amsterdam, Netherlands), 74, 188-196. [Google Scholar] [CrossRef] [PubMed]
[47] Almholt, K., Lund, L.R., Rygaard, J., et al. (2005) Reduced Metastasis of Transgenic Mammary Cancer in Urokinase-Deficient Mice. International Journal of Cancer, 113, 525-532. [Google Scholar] [CrossRef] [PubMed]
[48] Yan, D., Wang, H.W., Bowman, R.L., et al. (2016) STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation. Cell Reports, 16, 2914-2927. [Google Scholar] [CrossRef] [PubMed]
[49] Gil-Bernabé, A.M., Ferjancic, S., Tlalka, M., et al. (2012) Re-cruitment of Monocytes/Macrophages by Tissue Factor-Mediated Coagulation Is Essential for Metastatic Cell Survival and Premetastatic Niche Establishment in Mice. Blood, 119, 3164-3175. [Google Scholar] [CrossRef] [PubMed]
[50] Sanford, D.E., Belt, B.A., Panni, R.Z., et al. (2013) Inflam-matory Monocyte Mobilization Decreases Patient Survival in Pancreatic Cancer: A Role for Targeting the CCL2/CCR2 Axis. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 19, 3404-3415. [Google Scholar] [CrossRef
[51] Bockorny, B., Semenisty, V., Macarulla, T., et al. (2020) BL-8040, a CXCR4 Antagonist, in Combination with Pembrolizumab and Chemotherapy for Pancreatic Cancer: The COMBAT Trial. Nature Medicine, 26, 878-885. [Google Scholar] [CrossRef] [PubMed]
[52] Markiewski, M.M., Deangelis, R.A., Benencia, F., et al. (2008) Modulation of the Antitumor Immune Response by Complement. Nature Immunology, 9, 1225-1235. [Google Scholar] [CrossRef] [PubMed]
[53] Yancey, K.B., Lawley, T.J., Dersookian, M., et al. (1989) Analysis of the In-teraction of Human C5a and C5a des Arg with Human Monocytes and Neutrophils: Flow Cytometric and Chemotaxis Studies. The Journal of Investigative Dermatology, 92, 184-189. [Google Scholar] [CrossRef] [PubMed]
[54] Corrales, L., Ajona, D., Rafail, S., et al. (2012) Anaphylatoxin C5a Creates a Favorable Microenvironment for Lung Cancer Progression. Journal of Immunology (Baltimore, Md: 1950), 189, 4674-4683. [Google Scholar] [CrossRef] [PubMed]
[55] Janson, C., Jung, H., Ertl, L., et al. (2017) Inhibition of CCR2 Po-tentiates Checkpoint Inhibitor Immunotherapy in Murine Model of Pancreatic Cancer. Cancer Research, 77. [Google Scholar] [CrossRef
[56] Kumar, V., Donthireddy, L., Marvel, D., et al. (2017) Cancer-Associated Fibroblasts Neutralize the Anti-Tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell, 32, 654-668.e5. [Google Scholar] [CrossRef] [PubMed]
[57] Comito, G., Pons Segura, C., Taddei, M.L., et al. (2017) Zoledronic Acid Impairs Stromal Reactivity by Inhibiting M2-Macrophages Polarization and Prostate Cancer-Associated Fibroblasts. Oncotarget, 8, 118-132. [Google Scholar] [CrossRef] [PubMed]
[58] Wu, X., Schulte, B.C., Zhou, Y., et al. (2014) Depletion of M2-Like Tumor-Associated Macrophages Delays Cutaneous T-Cell Lymphoma Development in Vivo. The Journal of Investigative Dermatology, 134, 2814-2822. [Google Scholar] [CrossRef] [PubMed]
[59] Zhang, W., Zhu, X.D., Sun, H.C., et al. (2010) Depletion of Tu-mor-Associated Macrophages Enhances the Effect of Sorafenib in Metastatic Liver Cancer Models by Antimetastatic and Antiangiogenic Effects. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 16, 3420-3430. [Google Scholar] [CrossRef
[60] Germano, G., Frapolli, R., Belgiovine, C., et al. (2013) Role of Macrophage Targeting in the Antitumor Activity of Trabectedin. Cancer Cell, 23, 249-262. [Google Scholar] [CrossRef] [PubMed]
[61] Liguori, M., Buracchi, C., Pasqualini, F., et al. (2016) Functional TRAIL Receptors in Monocytes and Tumor-Associated Macrophages: A Possible Targeting Pathway in the Tumor Mi-croenvironment. Oncotarget, 7, 41662-41676. [Google Scholar] [CrossRef] [PubMed]
[62] La Fleur, L., Botling, J., He, F., et al. (2021) Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lym-phocyte Function. Cancer Research, 81, 956-967. [Google Scholar] [CrossRef
[63] Mantovani, A., Marchesi, F., Malesci, A., et al. (2017) Tumour-Associated Macrophages as Treatment Targets in Oncology. Nature Reviews Clinical Oncology, 14, 399-416. [Google Scholar] [CrossRef] [PubMed]
[64] Gallotta, M., Assi, H., Degagné, É., et al. (2018) Inhaled TLR9 Agonist Renders Lung Tumors Permissive to PD-1 Blockade by Promoting Optimal CD4 and CD8 T-Cell Interplay. Cancer Research, 78, 4943-4956. [Google Scholar] [CrossRef
[65] Karapetyan, L., Luke, J.J. and Davar, D. (2020) Toll-Like Receptor 9 Agonists in Cancer. OncoTargets and Therapy, 2020, 10039-10061. [Google Scholar] [CrossRef
[66] Kaneda, M.M., Messer, K.S., Ralainirina, N., et al. (2017) Corrigen-dum: PI3Kγ Is a Molecular Switch That Controls Immune Suppression. Nature, 542, 124. [Google Scholar] [CrossRef] [PubMed]
[67] Mirzaei, S., Gholami, M.H., Mahabady, M.K., et al. (2021) Pre-Clinical Investigation of STAT3 Pathway in Bladder Cancer: Paving the Way for Clinical Translation. Biomedicine & Pharma-cotherapy, 133, Article ID: 111077. [Google Scholar] [CrossRef] [PubMed]
[68] Chen, Y.H., Zhou, B.Y., Wu, G.C., et al. (2018) Effects of Ex-ogenous IL-37 on the Biological Characteristics of Human Lung Adenocarcinoma A549 Cells and the Chemotaxis of Regulatory T Cells. Cancer Biomarkers: Section A of Disease Markers, 21, 661-673. [Google Scholar] [CrossRef
[69] Zhang, Z., Zhang, J., He, P., et al. (2020) Interleukin-37 Suppresses Hepatocellular Carcinoma Growth through Inhibiting M2 Polarization of Tumor-Associated Macrophages. Molecular Immunology, 122, 13-20. [Google Scholar] [CrossRef] [PubMed]
[70] Chen, Y., Jin, H., Song, Y., et al. (2021) Targeting Tu-mor-Associated Macrophages: A Potential Treatment for Solid Tumors. Journal of Cellular Physiology, 236, 3445-3465. [Google Scholar] [CrossRef] [PubMed]