Tumour progression is modulated by the local microenvironment. This environment is populated by many immune cells, of which macrophages are among the most abundant. Clinical correlative data and a plethora of preclinical studies in mouse models of cancers have shown that tumour-associated macrophages (TAMs) play a cancer-promoting role. Within the primary tumour, TAMs promote tumour cell invasion and intravasation and tumour stem cell viability and induce angiogenesis. At the metastatic site, metastasis-associated macrophages promote extravasation, tumour cell survival and persistent growth, as well as maintain tumour cell dormancy in some contexts. In both the primary and metastatic sites, TAMs are suppressive to the activities of cytotoxic T and natural killer cells that have the potential to eradicate tumours. Such activities suggest that TAMs will be a major target for therapeutic intervention. In this Perspective article, we chronologically explore the evolution of our understanding of TAM biology put into the context of major enabling advances in macrophage biology.
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Metchnikoff, E. Ueber den Kampf der Zellen gegen Erysipelkokken, ein Beitrag zur Phagocytenlehre. Arch. Pathol. Anat. [Virchow’s Arch.] 107, 207–249 (1887).
Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation: Delivered at the Pasteur Institute in 1891 (Kegan Paul, Trench, Trübner & Co., Ltd, 1893).
Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).
Lipsick, J. A history of cancer research: tumor suppressor genes. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a035907 (2020).
Gerstung, M. et al. The evolutionary history of 2,658 cancers. Nature 578, 122–128 (2020).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Bissell, M. J. & Hines, W. C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320–329 (2011).
Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).
Brinster, R. L. The effect of cells transferred into the mouse blastocyst on subsequent development. J. Exp. Med. 140, 1049–1056 (1974).
Mintz, B. & Illmensee, K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc. Natl Acad. Sci. USA 72, 3585–3589 (1975).
Dolberg, D. S. & Bissell, M. J. Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature 309, 552–556 (1984).
Dolberg, D. S., Hollingsworth, R., Hertle, M. & Bissell, M. J. Wounding and its role in RSV-mediated tumor formation. Science 230, 676–678 (1985).
Kakiuchi, N. & Ogawa, S. Clonal expansion in non-cancer tissues. Nat. Rev. Cancer 21, 239–256 (2021).
Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588–602.e10 (2019).
Gentles, A. J. et al. Integrating tumor and stromal gene expression signatures with clinical indices for survival stratification of early-stage non-small cell lung cancer. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djv211 (2015).
Virchow, R. Die Krankhaften Geschwülste Vol. 1, 57–71 (Verlag von August Hirschwald,1863).
Underwood, J. C. Lymphoreticular infiltration in human tumours: prognostic and biological implications: a review. Br. J. Cancer 30, 538–548 (1974).
Balkwill, F. R. & Mantovani, A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin. Cancer Biol. 22, 33–40 (2012).
Tauber, A. I. Metchnikoff and the phagocytosis theory. Nat. Rev. Mol. Cell Biol. 4, 897–901 (2003).
Pollard, J. W. Trophic macrophages in development and disease. Nat. Rev. Immunol. 9, 259–270 (2009).
Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).
Kawai, Y., Smedsrod, B., Elvevold, K. & Wake, K. Uptake of lithium carmine by sinusoidal endothelial and Kupffer cells of the rat liver: new insights into the classical vital staining and the reticulo-endothelial system. Cell Tissue Res. 292, 395–410 (1998).
van Furth, R. et al. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull. World Health Organ. 46, 845–852 (1972).
Moore, M. A. & Metcalf, D. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br. J. Haematol. 18, 279–296 (1970).
Takahashi, K. & Naito, M. Development, differentiation, and proliferation of macrophages in the rat yolk sac. Tissue Cell 25, 351–362 (1993).
Takahashi, K., Yamamura, F. & Naito, M. Differentiation, maturation, and proliferation of macrophages in the mouse yolk sac: a light-microscopic, enzyme-cytochemical, immunohistochemical, and ultrastructural study. J. Leukoc. Biol. 45, 87–96 (1989).
Herbomel, P., Thisse, B. & Thisse, C. Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Dev. Biol. 238, 274–288 (2001).
Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
Lee, C. Z. W. & Ginhoux, F. Biology of resident tissue macrophages. Development https://doi.org/10.1242/dev.200270 (2022).
Bradley, T. R. & Metcalf, D. The growth of mouse bone marrow cells in vitro. Aust. J. Exp. Biol. Med. Sci. 44, 287–299 (1966).
Bradley, T. R., Stanley, E. R. & Sumner, M. A. Factors from mouse tissues stimulating colony growth of mouse bone marrow cells in vitro. Aust. J. Exp. Biol. Med. Sci. 49, 595–603 (1971).
Stanley, E. R. & Heard, P. M. Factors regulating macrophage production and growth conditioned by mouse L cells. J. Biol. Chem. 252, 4305–4312 (1977).
Kawasaki, E. S. et al. Molecular cloning of a complementary DNA encoding human marcophage-specific colony-stimulating factor (CSF-1). Science 230, 291–296 (1985).
Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).
Metcalf, D. The colony-stimulating factors and cancer. Nat. Rev. Cancer 10, 425–434 (2010).
Gearing, D. P., King, J. A., Gough, N. M. & Nicola, N. A. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 8, 3667–3676 (1989).
Sherr, C. J. et al. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41, 665–676 (1985).
Wiktor-Jedrzejczak, W. et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl Acad. Sci. USA 87, 4828–4832 (1990).
Cecchini, M. G. et al. Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120, 1357–1372 (1994).
Pollard, J. W. & Stanley, E. R. Pleiotropic roles for CSF-1 in development defined by the mouse mutation osteopetrotic (op). Adv. Dev. Biochem. 4, 153–193 (1996).
Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).
Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).
Dai, X. et al. Targeted disruption of the mouse CSF-1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primititive progenitor cell frequencies and reproductive defects. Blood 99, 111–120 (2002).
Stanley, E. et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl Acad. Sci. USA 91, 5592–5596 (1994).
Hibbs, M. L. et al. Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis. J. Immunol. 178, 6435–6443 (2007).
Tushinski, R. J. et al. Survival of mononuclear phagocytes depends on a lineage-specific growth factor that the differentiated cells selectively destroy. Cell 28, 71–81 (1982).
Webb, S. E., Pollard, J. W. & Jones, G. E. Direct observation and quantification of macrophage chemoattraction to the growth factor CSF-1. J. Cell Sci. 109, 793–803 (1996).
Chitu, V. et al. The PCH family member MAYP/PSTPIP2 directly regulates F-actin bundling and enhances filopodia formation and motility in macrophages. Mol. Biol. Cell 16, 2947–2959 (2005).
Mackaness, G. B. The immunological basis of acquired cellular resistance. J. Exp. Med. 120, 105–120 (1964).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Stein, M., Keshav, S., Harris, N. & Gordon, S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992).
Hamilton, J. A. & Achuthan, A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 34, 81–89 (2013).
Dalton, D. K. et al. Multiple defects of immune cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993).
Huang, S. et al. Immune response in mice that lack the interferon-γ receptor. Science 259, 1742–1745 (1993).
Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).
Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
Rollins, B. J. Chemokines. Blood 90, 909–928 (1997).
Propper, D. J. & Balkwill, F. R. Harnessing cytokines and chemokines for cancer therapy. Nat. Rev. Clin. Oncol. 19, 237–253 (2022).
Bottazzi, B. et al. Regulation of the macrophage content of neoplasms by chemoattractants. Science 220, 210–212 (1983).
Bottazzi, B., Walter, S., Govoni, D., Colotta, F. & Mantovani, A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J. Immunol. 148, 1280–1285 (1992).
Fidler, I. J. & Schroit, A. J. Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self. Biochim. Biophys. Acta 948, 151–173 (1988).
Mantovani, A., Ming, W. J., Balotta, C., Abdeljalil, B. & Bottazzi, B. Origin and regulation of tumor-associated macrophages: the role of tumor-derived chemotactic factor. Biochim. Biophys. Acta 865, 59–67 (1986).
Mantovani, A., Caprioli, V., Gritti, P. & Spreafico, F. Human mature macrophages mediate antibody-dependent cellular cytotoxicity on tumour cells. Transplantation 24, 291–293 (1977).
Rollins, B. J., Morrison, E. D. & Stiles, C. D. Cloning and expression of JE, a gene inducible by platelet-derived growth factor and whose product has cytokine-like properties. Proc. Natl Acad. Sci. USA 85, 3738–3742 (1988).
Matsushima, K., Larsen, C. G., DuBois, G. C. & Oppenheim, J. J. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J. Exp. Med. 169, 1485–1490 (1989).
Burnet, F. M. The concept of immunological surveillance. Prog. Exp. Tumor Res. 13, 1–27 (1970).
Prehn, R. T. The immune reaction as a stimulator of tumor growth. Science 176, 170–171 (1972).
Barnd, D. L., Lan, M. S., Metzgar, R. S. & Finn, O. J. Specific, major histocompatibility complex-unrestricted recognition of tumor-associated mucins by human cytotoxic T cells. Proc. Natl Acad. Sci. USA 86, 7159–7163 (1989).
Mantovani, A. Effects on in vitro tumor growth of murine macrophages isolated from sarcoma lines differing in immunogenicity and metastasizing capacity. Int. J. Cancer 22, 741–46 (1978).
Evans, R. Macrophage requirement for growth of a murine fibrosarcoma. Br. J. Cancer 37, 1086–1089 (1978).
Kadhim, S. A. & Rees, R. C. Enhancement of tumor growth in mice: evidence for the involvement of host macrophages. Cell. Immunol. 87, 259–269 (1984).
Hibbs, J. B. Jr, Vavrin, Z. & Taintor, R. R. L-arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J. Immunol. 138, 550–565 (1987).
Hibbs, J. B. Jr, Taintor, R. R., Vavrin, Z. & Rachlin, E. M. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem. Biophys. Res. Commun. 157, 87–94 (1988).
Palmer, R. M. & Moncada, S. A novel citrulline-forming enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem. Biophys. Res. Commun. 158, 348–352 (1989).
Lifsted, T. et al. Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int. J. Cancer 77, 640–644 (1998).
Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).
Mills, C. D., Shearer, J., Evans, R. & Caldwell, M. D. Macrophage arginine metabolism and the inhibition or stimulation of cancer. J. Immunol. 149, 2709–2714 (1992).
Mills, C. D. Molecular basis of ‘suppressor’ macrophages. Arginine metabolism via the nitric oxide synthetase pathway. J. Immunol. 146, 2719–2723 (1991).
Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173 (2000).
Mills, C. D. Anatomy of a discovery: M1 and M2 macrophages. Front. Immunol. 6, 212 (2015).
Sica, A. et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-κB activation in tumor-associated macrophages. J. Immunol. 164, 762–767 (2000).
Saccani, A. et al. p50 nuclear factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 66, 11432–11440 (2006).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549–555 (2002).
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A. & Locati, M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol. 229, 176–185 (2013).
Kacinski, B. M. et al. High level expression of fms proto-oncogene mRNA is observed in clinically aggressive human endometrial adenocarcinomas. Int. J. Radiat. Oncol. Biol. Phys. 15, 823–829 (1988).
Kacinski, B. M. et al. Ovarian adenocarcinomas express fms-complementary transcripts and fms antigen, often with coexpression of CSF-1. Am. J. Pathol. 137, 135–147 (1990).
Chambers, S. K., Kacinski, B. M., Ivins, C. M. & Carcangiu, M. L. Overexpression of epithelial macrophage colony-stimulating factor (CSF-1) and CSF-1 receptor: a poor prognostic factor in epithelial ovarian cancer, contrasted with a protective effect of stromal CSF-1. Clin. Cancer Res. 3, 999–1007 (1997).
Kluger, H. M. et al. Macrophage colony-stimulating factor-1 receptor expression is associated with poor outcome in breast cancer by large cohort tissue microarray analysis. Clin. Cancer Res 10, 173–177 (2004).
Scholl, S. M. et al. Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J. Natl Cancer Inst. 86, 120–126 (1994).
Tang, R. et al. M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumor cells: M-CSF mediated recruitment of tumour infiltrating monocytes? J. Cell. Biochem. 50, 350–356 (1992).
Smith, H. O. et al. The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma. Clin. Cancer Res. 1, 313–325 (1995).
Smith, H. O. et al. The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma. Mol. Oncol. 7, 41–54 (2013).
Ueno, T. et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin. Cancer Res. 6, 3282–3289 (2000).
Saji, H. et al. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer 92, 1085–1091 (2001).
Negus, R. P., Stamp, G. W., Hadley, J. & Balkwill, F. R. Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. Am. J. Pathol. 150, 1723–1734 (1997).
O’Connor, T. & Heikenwalder, M. CCL2 in the tumor microenvironment. Adv. Exp. Med. Biol. 1302, 1–14 (2021).
Leek, R. D. et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56, 4625–4629 (1996).
Visscher, D. W., Tabaczka, P., Long, D. & Crissman, J. D. Clinicopathologic analysis of macrophage infiltrates in breast carcinoma. Pathol. Res. Pract. 191, 1133–1139 (1995).
Yang, M., McKay, D., Pollard, J. W. & Lewis, C. E. Diverse functions of macrophages in different tumor microenvironments. Cancer Res. 78, 5492–5503 (2018).
O’Sullivan, C., Lewis, C. E., Harris, A. L. & McGee, J. O. Secretion of epidermal growth factor by macrophges associated with breast carcinoma. Lancet 342, 872–873 (1993).
Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L. & Lewis, C. E. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J. Pathol. 192, 150–158 (2000).
Lewis, C. E., Leek, R., Harris, A. & McGee, J. O. Cytokine regulation in breast cancer: the role of tumor-assosciated macrophages. J. Leukoc. Biol. 57, 747–751 (1995).
Leek, R. D. & Harris, A. L. Tumor-associated macrophages in breast cancer. J. Mammary Gland. Biol. Neoplasia 7, 177–189 (2002).
Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S. & Ruco, L. The origin and function of tumor-associated macrophages. Immunol. Today 13, 265–270 (1993).
Bingle, L., Brown, N. J. & Lewis, C. E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).
Zhang, Q. W. et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS ONE 7, e50946 (2012).
Yu, M. et al. Prognostic value of tumor-associated macrophages in pancreatic cancer: a meta-analysis. Cancer Manag. Res. 11, 4041–4058 (2019).
Dave, S. S. et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N. Engl. J. Med. 351, 2159–2169 (2004).
Beck, A. H. et al. The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin. Cancer Res. 15, 778–787 (2009).
Farinha, P. et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 106, 2169–2174 (2005).
Steidl, C. et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N. Engl. J. Med. 362, 875–885 (2010).
Steidl, C., Farinha, P. & Gascoyne, R. D. Macrophages predict treatment outcome in Hodgkin’s lymphoma. Haematologica 96, 186–189 (2011).
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
Gangoso, E. et al. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell 184, 2454–2470.e26 (2021).
Chen, C. et al. Cancer co-opts differentiation of B-cell precursors into macrophage-like cells. Nat. Commun. 13, 5376 (2022).
Pollard, J. W. & Hennighausen, L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc. Natl Acad. Sci. USA 91, 9312–9316 (1994).
Lang, R. A. & Bishop, J. M. Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 74, 453–462 (1993).
Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).
Scholl, S. M., Crocker, P., Tang, R., Pouillart, P. & Pollard, J. W. Is colony stimulating factor-1 a key mediator in breast cancer invasion and metastasis? Mol. Carcinog. 7, 207–211 (1993).
Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001).
Pyonteck, S. M. et al. Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. Oncogene https://doi.org/10.1038/onc.2011.337 (2011).
Strachan, D. C. et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8 T cells. Oncoimmunology 2, e26968 (2013).
Ryder, M. et al. Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS ONE 8, e54302 (2013).
Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 (2016).
Wyckoff, J. et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).
Wyckoff, J. B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).
Patsialou, A. et al. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 69, 9498–9506 (2009).
Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).
DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).
Goswami, S. et al. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin. Exp. Metastasis 26, 153–159 (2009).
Rohan, T. E. et al. Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/dju136 (2014).
Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).
Gocheva, V. et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 24, 241–255 (2010).
Sangaletti, S. et al. Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 68, 9050–9059 (2008).
Sunderkotter, C., Steinbrink, K., Goebeler, M., Bhardwaj, R. & Sorg, C. Macrophages and angiogenesis. J. Leukoc. Biol. 55, 410–422 (1994).
Leek, R. D. et al. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J. Pathol. 190, 430–436 (2000).
De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9, 789–795 (2003).
De Palma, M. & Naldini, L. Tie2-expressing monocytes (TEMs): novel targets and vehicles of anticancer therapy? Biochim. Biophys. Acta 1796, 5–10 (2009).
De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).
Jakab, M., Rostalski, T., Lee, K. H., Mogler, C. & Augustin, H. G. Tie2 receptor in tumor-infiltrating macrophages is dispensable for tumor angiogenesis and tumor relapse after chemotherapy. Cancer Res. 82, 1353–1364 (2022).
Folkman, J., Watson, K., Ingber, D. & Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989).
Lin, E. Y. et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 66, 11238–11246 (2006).
Yeo, E. J. et al. Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 74, 2962–2973 (2014).
Leek, R. D., Harris, A. L. & Lewis, C. E. Cytokine networks in solid human tumors: regulation of angiogenesis. J. Leukoc. Biol. 56, 423–435 (1994).
Lu, H. et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 16, 1105–1117 (2014).
Fan, Q. M. et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial–mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 352, 160–168 (2014).
Sharma, V. P. et al. Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination. Nat. Commun. 12, 7300 (2021).
Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).
Pollard, J. W. Tumor educated macrophages promote tumor progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).
Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Plaks, V. et al. Adaptive immune regulation of mammary postnatal organogenesis. Dev. Cell 34, 493–504 (2015).
Laviron, M. et al. Tumor-associated macrophage heterogeneity is driven by tissue territories in breast cancer. Cell Rep. 39, 110865 (2022).
Zhu, Y. et al. Tissue resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338 (2017).
Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6Chigh monocytes. Cancer Res 70, 5728–5739 (2010).
Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science https://doi.org/10.1126/science.1252510 (2014).
Arwert, E. N. et al. A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation. Cell Rep. 23, 1239–1248 (2018).
Lin, E. Y. et al. Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol. Oncol. 1, 288–302 (2007).
Qian, B. et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4, e6562 (2009).
Lu, X. & Kang, Y. Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J. Biol. Chem. 284, 29087–29096 (2009).
Chen, Q., Zhang, X. H. & Massague, J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 20, 538–549 (2011).
Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).
Kitamura, T. et al. Monocytes differentiate to immune suppressive precursors of metastasis-associated macrophages in mouse models of metastatic breast cancer. Front. Immunol. 8, 2004 (2017).
Qian, B. Z. et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J. Exp. Med. 212, 1433–1448 (2015).
Borriello, L. et al. Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells. Nat. Commun. 13, 626 (2022).
Kaplan, R. N., Psaila, B. & Lyden, D. Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Rev. 25, 521–529 (2006).
Gil-Bernabe, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).
Ma, R. Y. et al. Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J. Exp. Med. https://doi.org/10.1084/jem.20191820 (2020).
Loyher, P. L. et al. Macrophages of distinct origins contribute to tumor development in the lung. J. Exp. Med. 215, 2536–2553 (2018).
Casanova-Acebes, M. et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature 595, 578–584 (2021).
Jacome-Galarza, C. E. et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 568, 541–545 (2019).
Yin, J. J. et al. TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999).
Kakonen, S. M. & Mundy, G. R. Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97, 834–839 (2003).
Biswas, S. et al. Anti-transforming growth factor β antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. PLoS ONE 6, e27090 (2011).
Güç, E. & Pollard, J. W. Redefining macrophage and neutrophil biology in the metastatic cascade. Immunity 54, 885–902 (2021).
Hoyer, F. F. et al. Tissue-specific macrophage responses to remote injury impact the outcome of subsequent local immune challenge. Immunity 51, 899–914.e7 (2019).
Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).
Maru, Y. Premetastasis. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a036897 (2020).
Rodriguez-Tirado, C. et al. Interleukin 4 controls the pro-tumoral role of macrophages in mammary cancer pulmonary metastasis in mice. Cancers https://doi.org/10.3390/cancers14174336 (2022).
Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).
Lopez-Yrigoyen, M., Cassetta, L. & Pollard, J. W. Macrophage targeting in cancer. Ann. N. Y. Acad. Sci. 1499, 18–41 (2021).
Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).
Dhupkar, P., Gordon, N., Stewart, J. & Kleinerman, E. S. Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases. Cancer Med. 7, 2654–2664 (2018).
Jing, W. et al. Breast cancer cells promote CD169+ macrophage-associated immunosuppression through JAK2-mediated PD-L1 upregulation on macrophages. Int. Immunopharmacol. 78, 106012 (2020).
Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).
Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).
Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).
Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).
Wellenstein, M. D. et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019).
Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809–821 (2014).
Mantovani, A., Marchesi, F., Jaillon, S., Garlanda, C. & Allavena, P. Tumor-associated myeloid cells: diversity and therapeutic targeting. Cell. Mol. Immunol. 18, 566–578 (2021).
Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).
Pucci, F. et al. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood ‘resident’ monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood 114, 901–914 (2009).
Ojalvo, L. S., King, W., Cox, D. & Pollard, J. W. High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors. Am. J. Pathol. 174, 1048–1064 (2009).
Ojalvo, L. S., Whittaker, C. A., Condeelis, J. S. & Pollard, J. W. Gene expression analysis of macrophages that facilitate tumor invasion supports a role for Wnt-signaling in mediating their activity in primary mammary tumors. J. Immunol. 184, 702–712 (2010).
Hughes, R. et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res 75, 3479–3491 (2015).
Kitamura, T. et al. Mammary tumor cells with high metastatic potential are hypersensitive to macrophage-derived HGF. Cancer Immunol. Res. 7, 2052–2064 (2019).
Zheng, W. et al. Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases. Wellcome Open Res. 6, 52 (2021).
Pombo Antunes, A. R. et al. Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat. Neurosci. 24, 595–610 (2021).
Mulder, K. et al. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease. Immunity 54, 1883–1900.e5 (2021).
Cheng, S. et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell 184, 792–809.e23 (2021).
Ma, R. Y., Black, A. & Qian, B. Z. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol. 43, 546–563 (2022).
Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-κB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006).
Bainbridge, M. N. et al. Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics 7, 246 (2006).
Tang, F. et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat. Methods 6, 377–382 (2009).
Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).
Zilionis, R. et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 50, 1317–1334.e10 (2019).
Wigerblad, G. et al. Single-cell analysis reveals the range of transcriptional states of circulating human neutrophils. J. Immunol. 209, 772–782 (2022).
Ramos, N. R. et al. Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer. Cell 185, 1189–1207.e25 (2022).
Meylan, M. et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity 55, 527–541.e5 (2022).
Moncada, R. et al. Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas. Nat. Biotechnol. 38, 333–342 (2020).
Andersson, A. et al. Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions. Nat. Commun. 12, 6012 (2021).
Hunter, M. V., Moncada, R., Weiss, J. M., Yanai, I. & White, R. M. Spatially resolved transcriptomics reveals the architecture of the tumor–microenvironment interface. Nat. Commun. 12, 6278 (2021).
Kitamura, T., Qian, B. Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).
Xiao, M. et al. Tumor-associated macrophages: critical players in drug resistance of breast cancer. Front. Immunol. 12, 799428 (2021).
Shree, T. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011).
Shiao, S. L. et al. TH2-polarized CD4+ T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol. Res. 3, 518–525 (2015).
Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74, 5057–5069 (2014).
Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).
Guerriero, J. L. et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543, 428–432 (2017).
Pfirschke, C. et al. Macrophage-targeted therapy unlocks antitumoral cross-talk between IFNγ-secreting lymphocytes and IL12-producing dendritic cells. Cancer Immunol. Res. 10, 40–55 (2022).
Gubin, M. M. et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175, 1014–1030.e19 (2018).
Kashyap, A. S. et al. Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy. Proc. Natl Acad. Sci. USA 117, 541–551 (2020).
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
Li, D. K. & Wang, W. Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies. Oncol. Lett. 20, 176 (2020).
Mills, C. D. & Ley, K. M1 and M2 macrophages: the chicken and the egg of immunity. J. Innate Immun. 6, 716–726 (2014).
Zhai, L. et al. Immunosuppressive IDO in cancer: mechanisms of action, animal models, and targeting strategies. Front. Immunol. 11, 1185 (2020).
Tang, K., Wu, Y. H., Song, Y. & Yu, B. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J. Hematol. Oncol. 14, 68 (2021).
Mitchell, T. C. et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol. 36, 3223–3230 (2018).
Luke, J. J. et al. BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (nivo): updated safety across all tumor cohorts and efficacy in advanced bladder cancer (advBC). J. Clin. Oncol. 37, 358–358 (2019).
Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-022-00620-6 (2022).
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/nrclinonc.2016.217 (2017).
Hoves, S. et al. Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. J. Exp. Med. 215, 859–876 (2018).
Cassetta, L. & Pollard, J. W. Targeting macrophages: therapeutic approaches in cancer. Nat. Rev. Drug. Discov. 17, 887–904 (2018).
Gschwandtner, M., Derler, R. & Midwood, K. S. More than just attractive: how CCL2 influences myeloid cell behavior beyond chemotaxis. Front. Immunol. 10, 2759 (2019).
Sandhu, S. K. et al. A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother. Pharmacol. 71, 1041–1050 (2013).
Southwest Oncology Group. S0916, MLN1202 in treating patients with bone metastases. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01015560 (2018).
Argyle, D. & Kitamura, T. Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front. Immunol. 9, 2629 (2018).
Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).
Cassier, P. A. et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Lancet Oncol. 16, 949–956 (2015).
Tap, W. D. et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N. Engl. J. Med. 373, 428–437 (2015).
Daiichi Sankyo, Inc. Phase 3 study of pexidartinib for pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS) (ENLIVEN). ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02371369 (2022).
Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23, 249–262 (2013).
Barone, A. et al. FDA approval summary: trabectedin for unresectable or metastatic liposarcoma or leiomyosarcoma following an anthracycline-containing regimen. Clin. Cancer Res. 23, 7448–7453 (2017).
Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).
Sikic, B. I. et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 37, 946–953 (2019).
Jiang, Z., Sun, H., Yu, J., Tian, W. & Song, Y. Targeting CD47 for cancer immunotherapy. J. Hematol. Oncol. 14, 180 (2021).
Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).
Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).
Coley, W. B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3, 1–48 (1910).
Dudek, A. Z. et al. First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin. Cancer Res. 13, 7119–7125 (2007).
Link, B. K. et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma. J. Immunother. 29, 558–568 (2006).
Morales, A. & Eidinger, D. Bacillus Calmette–Guerin in the treatment of adenocarcinoma of the kidney. J. Urol. 115, 377–380 (1976).
Pahlavanneshan, S., Sayadmanesh, A., Ebrahimiyan, H. & Basiri, M. Toll-like receptor-based strategies for cancer immunotherapy. J. Immunol. Res. 2021, 9912188 (2021).
Ribas, A. et al. Overcoming PD-1 blockade resistance with CpG-A Toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma. Cancer Discov. 11, 2998–3007 (2021).
Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).
Carisma Therapeutics Inc. CAR-macrophages for the treatment of HER2 overexpressing solid tumors. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04660929 (2022).
Hanno, P. M., Buehler, J. & Wein, A. J. Use of amitriptyline in the treatment of interstitial cystitis. J. Urol. 141, 846–848 (1989).
Lamm, D. L. et al. Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol. 124, 38–42 (1980).
Stewart, T. A., Pattengale, P. K. & Leder, P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38, 627–637 (1984).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomovirus middle T oncogenes: a transgenic mouse mode of a metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).
Lin, E. Y. et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163, 2113–2126 (2003).
McFadden, D. G. et al. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc. Natl Acad. Sci. USA 113, E6409–E6417 (2016).
Ponz-Sarvise, M., Tuveson, D. A. & Yu, K. H. Mouse models of pancreatic ductal adenocarcinoma. Hematol. Oncol. Clin. North. Am. 29, 609–617 (2015).
Boissonnas, A. & Combadiere, C. Modulating the tumor-associated macrophage landscape. Nat. Immunol. 23, 481–482 (2022).
Austyn, J. M. & Gordon, S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur. J. Immunol. 11, 805–815 (1981).
Hume, D. A., Halpin, D., Charlton, H. M. & Gordon, S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: macrophages of endocrine organs. Proc. Natl Acad. Sci. USA 81, 4174–4177 (1984).
Lee, S.-H., Starkey, P. M. & Gordon, S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunocytochemical studies with monoclonal antibody F4/80. J. Exp. Med 161, 475–489 (1988).
Huang, Y. K. et al. Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry. Nat. Commun. 10, 3928 (2019).
Fernandez, A., Thompson, E. J., Pollard, J. W., Kitamura, T. & Vendrell, M. A fluorescent activatable AND-gate chemokine CCL2 enables in vivo detection of metastasis-associated macrophages. Angew. Chem. Int. Ed. Engl. 58, 16894–16898 (2019).
Himes, S. R. et al. A highly conserved c-fms gene intronic element controls macrophage-specific and regulated expression. J. Leukoc. Biol. 70, 812–820 (2001).
Sasmono, R. T. et al. A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101, 1155–1163 (2003).
Ovchinnikov, D. A. et al. Expression of Gal4-dependent transgenes in cells of the mononuclear phagocyte system labeled with enhanced cyan fluorescent protein using Csf1r-Gal4VP16/UAS-ECFP double-transgenic mice. J. Leukoc. Biol. 83, 430–433 (2008).
Grabert, K. et al. A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system. J. Immunol. 205, 3154–3166 (2020).
Entenberg, D. et al. Imaging tumor cell movement in vivo. Curr. Protoc. Cell Biol. https://doi.org/10.1002/0471143030.cb1907s58 (2013).
Entenberg, D. et al. Subcellular resolution optical imaging in the lung reveals early metastatic proliferation and motility. Intravital https://doi.org/10.1080/21659087.2015.1086613 (2015).
Geissmann, F., Jung, S. & Littman, D. R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).
Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).
Qiao, S., Qian, Y., Xu, G., Luo, Q. & Zhang, Z. Long-term characterization of activated microglia/macrophages facilitating the development of experimental brain metastasis through intravital microscopic imaging. J. Neuroinflamm. 16, 4 (2019).
Faust, N., Varas, F., Kelly, L. M., Heck, S. & Graf, T. Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96, 719–726 (2000).
Deng, L. et al. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am. J. Pathol. 176, 952–967 (2010).
Burnett, S. H. et al. Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene. J. Leukoc. Biol. 75, 612–623 (2004).
Li, J., Chen, K., Zhu, L. & Pollard, J. W. Conditional deletion of the colony stimulating factor-1 receptor (c-fms proto-oncogene) in mice. Genesis 44, 328–335 (2006).
Kitamura, T., Doughty-Shenton, D., Pollard, J. W. & Carragher, N. O. Real time detection of in vitro tumor cell apoptosis induced by CD8+ T cells to study immune suppressive functions of tumor-infiltrating myeloid cells. J. Vis. Exp. https://doi.org/10.3791/58841 (2019).
Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 8, 265–277 (1999).
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
Liu, Z. et al. Fate mapping via Ms4a3-expression history traces monocyte-derived cells. Cell 178, 1509–1525 (2019).
Hume, D. A. Applications of myeloid-specific promoters in transgenic mice support in vivo imaging and functional genomics but do not support the concept of distinct macrophage and dendritic cell lineages or roles in immunity. J. Leukoc. Biol. 89, 525–538 (2011).
Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).
Shukla, C. J. et al. Laser-capture microdissection in prostate cancer research: establishment and validation of a powerful tool for the assessment of tumour-stroma interactions. BJU Int 101, 765–774 (2008).
Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat. Med. 14, 518–527 (2008).
Cassetta, L. et al. Isolation of mouse and human tumor-associated macrophages. Adv. Exp. Med. Biol. 899, 211–229 (2016).
Tsujikawa, T. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep. 19, 203–217 (2017).
Lewis, C. E. & Pollard, J. W. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66, 605–612 (2006).
Matusiak, M. et al. A spatial map of human macrophage niches links tissue location with function. Preprint at bioRxiv https://doi.org/10.1101/2022.08.18.504434 (2022).
The authors thank The Wellcome Trust 101067/Z/13/Z (J.W.P.), MRC Centre grant MR/N022556/1 (J.W.P.) and CRUK programme grant C17950/A26783 (J.W.P.). The authors also thank C. Ries for her valuable insights on TAM targeting strategies.
J.W.P. is a cofounder and shareholder in and on the board of Macomics, an immuno-oncology company. L.C. is a founder, shareholder and is VP Immunology for Macomics.
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- Adaptive immune responses
The immune response mediated by recognition of non-self by lymphocytes, leading to an antigen-specific immune response and the generation of memory cells that fight against future infections.
(Cluster of differentiation 40). This member of the tumour necrosis factor receptor family is a costimulatory protein found on antigen-presenting cells and is required for their activation.
Small chemotactic signalling proteins secreted by cells to induce migration of stromal and cancerous cells to facilitate homeostasis and tissue repair.
- Complement activation
A part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microorganisms and damaged cells from an organism, promote inflammation and attack the cell membrane of the pathogen.
- Dendritic cells
Phagocytic mononuclear cells with finger-like projections that are specialized in migration and antigen presentation.
- Humoral immunity
Adaptive immunity that is mediated by B cell-derived antibodies and macromolecules, including complement proteins, and certain antimicrobial peptides, located in extracellular fluids.
- Innate immune system
The first response of the body to foreign substrates; it is not antigen recognition-driven, requires sensing of pattern molecules (either damage-associated or pathogen-associated) and can modulate the cells of the second immunity strategy (adaptive immunity).
- Lymphoreticular infiltration
The presence of bone marrow progenitors, blood monocytes, tissue macrophages, lymphocytes, plasma cells, polymorphonuclear leukocytes and mast cells in the tumour.
- M1 macrophages
Generally referred to as ‘activated’ macrophages, M1 are responsive to interferon-γ and lipopolysaccharide, and often considered antitumoural.
- M2 macrophages
Generally known as ‘alternatively activated’ macrophages, M2 responds to IL-4 and IL-10 and typically regarded as pro-tumoural.
Bone marrow-derived progenitors of macrophages and a subset of dendritic cells, found in the circulation, and classified by their differentiation (classical, intermediate and non-classical).
- Mononuclear phagocytes
(MNPs). Phagocytic cells belonging to the immune system and derived from the bone marrow, mostly monocytes and macrophages.
- Mouse mammary tumour virus-polyoma middle tumour-antigen
(MMTV-PyMT). Mouse model of mammary cancer caused by expression of the PyMT oncoprotein in a mammary epithelial-restricted fashion; this model is autochthonous, progressive and metastatic.
Bone-marrow-derived cells from myeloblasts include basophils, eosinophils, neutrophils and macrophages.
- Tenosynovial giant cell tumour
Non-malignant tumours in humans that often develop in the synovium caused by an activating gene translocation in the colony-stimulating factor 1 gene (CSF1) that results in excessive CSF1 production and thus infiltration of macrophages.
On the basis of extremes of immune responses, TH1 response is characterized by the production of interferon-γ, IL-2 and IL-12 and the ability to respond to bacterial and viral pathogens. TH1 responses generally confer cancer resistance.
TH2 responses characterized by production of IL-4, IL-5 and IL-10, and their role in tissue repair. TH2 responses generally confer cancer susceptibility.
- Tumour microenvironment
(TME). The non-cancerous portion surrounding the tumour consisting of fibroblast, endothelial and immune cells as well as extracellular matrix and blood vessels (also referred to as ‘stroma’).
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Cassetta, L., Pollard, J.W. A timeline of tumour-associated macrophage biology. Nat Rev Cancer 23, 238–257 (2023). https://doi.org/10.1038/s41568-022-00547-1
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