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The complex role of tumor-infiltrating macrophages

Abstract

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being re-discovered as regulators of several diseases, including cancer. Tumor-associated macrophages (TAMs) represent the most abundant innate immune population in the tumor microenvironment (TME). Macrophages are professional phagocytic cells of the hematopoietic system specializing in the detection, phagocytosis and destruction of bacteria and other harmful micro-organisms, apoptotic cells and metabolic byproducts. In contrast to these healthy macrophage functions, TAMs support cancer cell growth and metastasis and mediate immunosuppressive effects on the adaptive immune cells of the TME. Cancer is one of the most potent insults on macrophage physiology, inducing changes that are intimately linked with disease progression. In this Review, we outline hallmarks of TAMs and discuss the emerging mechanisms that contribute to their pathophysiological adaptations and the vulnerabilities that provide attractive targets for therapeutic exploitation in cancer.

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Fig. 1: In tumor-bearing hosts, tumor-released factors drive increased production and output of classical Ly6C+ monocytes and MDSCs from myeloid progenitors of the BM.
Fig. 2: Recruitment of BM-derived monocytes in tumors and subsequent conversion to TAMs requires activation of α4β1 integrin.
Fig. 3: Cancer-related inflammation is initiated by hematopoietic growth factors, cytokines, and chemokines produced by cancer cells as a consequence of oncogene-mediated malignant transformation.
Fig. 4: Changes of TAMs during cancer immunoediting.

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Acknowledgements

This work was supported by NIH grants R01CA238263 (V.A.B.) and R01CA229784 (A. Charest and V.A.B.).

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A. Christofides, L.S., A.Y., and C.C. wrote the main sections of the manuscript. A. Charest generated sections of the manuscript related to glioblastoma. V.A.B. generated sections of the manuscript, prepared figures, guided the co-authors and was responsible for the organization of the document.

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Correspondence to Vassiliki A. Boussiotis.

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V.A.B. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako. The authors declare no other competing interests.

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Christofides, A., Strauss, L., Yeo, A. et al. The complex role of tumor-infiltrating macrophages. Nat Immunol 23, 1148–1156 (2022). https://doi.org/10.1038/s41590-022-01267-2

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