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).
Komohara, Y., Jinushi, M. & Takeya, M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 105, 1–8 (2014).
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
Canli, O. et al. Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis. Cancer Cell 32, 869–883 (2017).
Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).
Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).
Coffelt, S. B. & de Visser, K. E. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol. 36, 198–216 (2015).
Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447–462 (2016).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014). This study describes a role for CSF1R in regulating the polarization of tumour macrophages rather than simply recruiting them into tumours.
Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).
Olson, O. C., Kim, H., Quail, D. F., Foley, E. A. & Joyce, J. A. Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep. 19, 101–113 (2017).
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).
Bonnardel, J. & Guilliams, M. Developmental control of macrophage function. Curr. Opin. Immunol. 50, 64–74 (2018).
Epelman, S., Lavine, K. J. & Randolph, G. J. Origin and functions of tissue macrophages. Immunity 41, 21–35 (2014).
Lavin, Y., Mortha, A., Rahman, A. & Merad, M. Regulation of macrophage development and function in peripheral tissues. Nat. Rev. Immunol. 15, 731–744 (2015).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
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).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).
Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012). This study identifies tissue-resident macrophages as having HSC-independent origins in mice.
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This study identifies microglia as having an embryonic origin in mice.
Calderon, B. et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J. Exp. Med. 212, 1497–1512 (2015).
Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).
Gibbings, S. L. et al. Transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages. Blood 126, 1357–1366 (2015).
Loyher, P. L. et al. Macrophages of distinct origins contribute to tumor development in the lung. J. Exp. Med. 215, 2536–2553 (2018).
Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).
Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).
Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323–338 (2017). This study describes a functional role for tissue-resident macrophages in tumour growth, an unexpected result given the prominence of the recruited population.
Bowman, R. L. et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 17, 2445–2459 (2016).
Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70, 5728–5739 (2010).
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).
Chen, Z. et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 77, 2266–2278 (2017).
Henze, A. T. & Mazzone, M. The impact of hypoxia on tumor-associated macrophages. J. Clin. Invest. 126, 3672–3679 (2016).
Doedens, A. L. et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T cell function and promotes tumor progression. Cancer Res. 70, 7465–7475 (2010).
Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010).
Casazza, A. et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013). This study demonstrates the importance of tumour hypoxia as a regulator of the immunosuppressive nature of macrophages.
Wallerius, M. et al. Guidance molecule SEMA3A restricts tumor growth by differentially regulating the proliferation of tumor-associated macrophages. Cancer Res. 76, 3166–3178 (2016).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014). This study finds that altered tumour metabolism contributes to the pro-tumour phenotype of macrophages.
Geeraerts, X., Bolli, E., Fendt, S. M. & Van Ginderachter, J. A. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front. Immunol. 8, 289 (2017).
Freemerman, A. J. et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289, 7884–7896 (2014).
Wang, F. et al. Glycolytic stimulation is not a requirement for M2 macrophage differentiation. Cell Metab. 28, 463–475 (2018).
Huang, S. C. et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45, 817–830 (2016).
Wenes, M. et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 24, 701–715 (2016).
Penny, H. L. et al. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology 5, e1191731 (2016).
Jones, R. S. & Morris, M. E. Monocarboxylate transporters: therapeutic targets and prognostic factors in disease. Clin. Pharmacol. Ther. 100, 454–463 (2016).
Bohn, T. et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat. Immunol. 19, 1319–1329 (2018).
El-Kenawi, A. et al. Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer. Preprint at bioRxiv https://doi.org/10.1101/478420 (2018).
Radu, C. G., Nijagal, A., McLaughlin, J., Wang, L. & Witte, O. N. Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc. Natl Acad. Sci. USA 102, 1632–1637 (2005).
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).
Chomarat, P., Banchereau, J., Davoust, J. & Palucka, A. K. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat. Immunol. 1, 510–514 (2000).
Wu, M. H. et al. Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin. Cancer Res. 17, 1306–1316 (2011).
Torres, S. et al. Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin. Cancer Res. 19, 6006–6019 (2013).
Mathew, E. et al. Mesenchymal stem cells promote pancreatic tumor growth by inducing alternative polarization of macrophages. Neoplasia 18, 142–151 (2016).
Kim, J. H. et al. The role of myofibroblasts in upregulation of S100A8 and S100A9 and the differentiation of myeloid cells in the colorectal cancer microenvironment. Biochem. Biophys. Res. Commun. 423, 60–66 (2012).
Mace, T. A. et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 73, 3007–3018 (2013).
Kumar, V. et al. CD45 phosphatase inhibits STAT3 transcription factor activity in myeloid cells and promotes tumor-associated macrophage differentiation. Immunity 44, 303–315 (2016).
Wang, Q. et al. Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α. Nat. Commun. 9, 559 (2018).
Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).
Song, L. et al. Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J. Clin. Invest. 119, 1524–1536 (2009).
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479 (2018).
Givel, A. M. et al. miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat. Commun. 9, 1056 (2018).
Zhou, W. et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat. Cell Biol. 17, 170–182 (2015).
Pickup, M. W., Mouw, J. K. & Weaver, V. M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15, 1243–1253 (2014).
Stahl, M. et al. Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation. PLOS ONE 8, e81382 (2013).
Wesley, R. B. 2nd, Meng, X., Godin, D. & Galis, Z. S. Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler Thromb. Vasc. Biol. 18, 432–440 (1998).
Meyaard, L. The inhibitory collagen receptor LAIR-1 (CD305). J. Leukoc. Biol. 83, 799–803 (2008).
McWhorter, F. Y., Davis, C. T. & Liu, W. F. Physical and mechanical regulation of macrophage phenotype and function. Cell. Mol. Life Sci. 72, 1303–1316 (2015).
Van Goethem, E., Poincloux, R., Gauffre, F., Maridonneau-Parini, I. & Le Cabec, V. Matrix architecture dictates three-dimensional migration modes of human macrophages: differential involvement of proteases and podosome-like structures. J. Immunol. 184, 1049–1061 (2010).
Sulzmaier, F. J., Jean, C. & Schlaepfer, D. D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer 14, 598–610 (2014).
Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).
Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016).
Sorokin, L. The impact of the extracellular matrix on inflammation. Nat. Rev. Immunol. 10, 712–723 (2010).
Tang, M. et al. Toll-like receptor 2 activation promotes tumor dendritic cell dysfunction by regulating IL-6 and IL-10 receptor signaling. Cell Rep. 13, 2851–2864 (2015).
Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009).
Kobayashi, N. et al. Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization. Cancer Res. 70, 7073–7083 (2010).
Jameson, J. M., Cauvi, G., Sharp, L. L., Witherden, D. A. & Havran, W. L. Gammadelta T cell-induced hyaluronan production by epithelial cells regulates inflammation. J. Exp. Med. 201, 1269–1279 (2005).
Lee-Sayer, S. S. et al. The where, when, how, and why of hyaluronan binding by immune cells. Front. Immunol. 6, 150 (2015).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Huber, R. et al. Tumour hypoxia promotes melanoma growth and metastasis via high mobility group Box-1 and M2-like macrophages. Sci. Rep. 6, 29914 (2016).
Roberts, A. W. et al. Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells. Immunity 47, 913–927 (2017).
Graham, D. K., DeRyckere, D., Davies, K. D. & Earp, H. S. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer 14, 769–785 (2014).
Cook, R. S. et al. MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis. J. Clin. Invest. 123, 3231–3242 (2013). This study describes how recognition of dying tumour cells by macrophages acts to suppress antitumour immunity.
Crittenden, M. R. et al. Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy. Oncotarget 7, 78653–78666 (2016).
Ubil, E. et al. Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. J. Clin. Invest. 128, 2356–2369 (2018).
Ruffell, B., Affara, N. I. & Coussens, L. M. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 33, 119–126 (2012).
Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).
Marigo, I. et al. T cell cancer therapy requires CD40-CD40L activation of tumor necrosis factor and inducible nitric-oxide-synthase-producing dendritic cells. Cancer Cell 30, 377–390 (2016).
Klug, F. et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589–602 (2013). This study is one of the few to describe macrophages as promoting antitumour immunity, in this case, during low-dose irradiation.
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).
Shiao, S. L. et al. TH2-polarized CD4+ T cells and macrophages limit efficacy of radiotherapy. Cancer Immunol. Res. 3, 518–525 (2015).
Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).
Kryczek, I. et al. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res. 67, 8900–8905 (2007).
Coffelt, S. B. et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).
Shahrara, S., Pickens, S. R., Dorfleutner, A. & Pope, R. M. IL-17 induces monocyte migration in rheumatoid arthritis. J. Immunol. 182, 3884–3891 (2009).
Jovanovic, D. V. et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-β and TNF-α, by human macrophages. J. Immunol. 160, 3513–3521 (1998).
Greenlee-Wacker, M. C. Clearance of apoptotic neutrophils and resolution of inflammation. Immunol. Rev. 273, 357–370 (2016).
Andreu, P. et al. FcRγ activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 17, 121–134 (2010).
de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).
Affara, N. I. et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25, 809–821 (2014).
Gunderson, A. J. et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 6, 270–285 (2016).
Kaneda, M. M. et al. Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression. Cancer Discov. 6, 870–885 (2016).
Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016). This is one of several studies showing that targeting downstream kinases can alter macrophage phenotype and improve the T cell response against tumours.
DeNardo, D. G. et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
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). This study describes how macrophages can indirectly suppress a T cell response by reducing IL-12 expression in tumour-associated dendritic cells.
Kusmartsev, S. & Gabrilovich, D. I. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J. Immunol. 174, 4880–4891 (2005).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Geiger, R. et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016).
Rodriguez, P. C. et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T cell receptor expression and antigen-specific T cell responses. Cancer Res. 64, 5839–5849 (2004).
Chang, C. I., Liao, J. C. & Kuo, L. Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Res. 61, 1100–1106 (2001).
Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).
Lu, T. et al. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J. Clin. Invest. 121, 4015–4029 (2011).
Lu, T. & Gabrilovich, D. I. Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin. Cancer Res. 18, 4877–4882 (2012).
Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828–835 (2007). This study identifies nitration of the T cell receptor as a mechanism by which reactive oxygen and nitrogen species can suppress the T cell response against cancer.
Zea, A. H. et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 65, 3044–3048 (2005).
Munder, M. et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105, 2549–2556 (2005).
Lin, H. et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J. Clin. Invest. 128, 805–815 (2018).
Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009). This study finds that PDL1 expression by myeloid cells negatively correlates with patient survival, suggesting that host expression of PDL1 is an important contributor to immune suppression.
Tang, H. et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J. Clin. Invest. 128, 580–588 (2018).
Ceeraz, S., Nowak, E. C. & Noelle, R. J. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol. 34, 556–563 (2013).
Li, J. et al. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8+ T cells. Immunity 48, 773–786 (2018).
Kreymborg, K. et al. Ablation of B7-H3 but not B7-H4 Results in highly increased tumor burden in a murine model of spontaneous prostate cancer. Cancer Immunol. Res. 3, 849–854 (2015).
Rahbar, R. et al. B7-H4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity. Cancer Immunol. Res. 3, 184–195 (2015).
Smith, L. K. et al. Interleukin-10 directly inhibits CD8+ T cell function by enhancing N-glycan branching to decrease antigen sensitivity. Immunity 48, 299–312 (2018).
Demotte, N. et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 28, 414–424 (2008).
Henderson, N. C. et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am. J. Pathol. 172, 288–298 (2008).
Schuette, V. et al. Mannose receptor induces T cell tolerance via inhibition of CD45 and up-regulation of CTLA-4. Proc. Natl Acad. Sci. USA 113, 10649–10654 (2016).
Stockmann, C. et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 456, 814–818 (2008).
Hughes, R. et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75, 3479–3491 (2015).
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).
Sato, E., Simpson, K. L., Grisham, M. B., Koyama, S. & Robbins, R. A. Effects of reactive oxygen and nitrogen metabolites on RANTES- and IL-5-induced eosinophil chemotactic activity in vitro. Am. J. Pathol. 155, 591–598 (1999).
Sato, E., Simpson, K. L., Grisham, M. B., Koyama, S. & Robbins, R. A. Effects of reactive oxygen and nitrogen metabolites on MCP-1-induced monocyte chemotactic activity in vitro. Am. J. Physiol. 277, L543–L549 (1999).
Molon, B. et al. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208, 1949–1962 (2011). Expanding upon the impact of reactive nitrogen species on the TME, this study finds that CCL2 nitration negatively impacts T cell infiltration.
Franciszkiewicz, K., Boissonnas, A., Boutet, M., Combadiere, C. & Mami-Chouaib, F. Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response. Cancer Res. 72, 6325–6332 (2012).
Nielsen, S. R. et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat. Cell Biol. 18, 549–560 (2016).
Quaranta, V. et al. Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer. Cancer Res. 78, 4253–4269 (2018).
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).
Kelly, A. et al. Human monocytes and macrophages regulate immune tolerance via integrin alphavbeta8-mediated TGFβ activation. J. Exp. Med. 215, 2725–2736 (2018).
de Mingo Pulido, A. et al. TIM-3 regulates CD103+ dendritic cell function and response to chemotherapy in breast cancer. Cancer Cell 33, 60–74 (2018).
Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).
Peranzoni, E. et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc. Natl Acad. Sci. USA 115, E4041–E4050 (2018).
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).
Salmon, H. et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).
Roberts, E. W. et al. Critical role for CD103+/CD141+ dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell 30, 324–336 (2016).
Cunha, L. D. et al. LC3-associated phagocytosis in myeloid cells promotes tumor immune tolerance. Cell 175, 429–441 (2018).
Ahn, J., Xia, T., Rabasa Capote, A., Betancourt, D. & Barber, G. N. Extrinsic phagocyte-dependent STING signaling dictates the immunogenicity of dying cells. Cancer Cell 33, 862–873 (2018).
Han, C. Z. et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 539, 570–574 (2016).
Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1 R inhibition in gliomas. Science 352, aad3018 (2016).
Gupta, P. et al. Tissue-resident CD169+ macrophages form a crucial front line against plasmodium infection. Cell Rep. 16, 1749–1761 (2016).
van Dinther, D. et al. Functional CD169 on macrophages mediates interaction with dendritic cells for CD8+ T Cell cross-priming. Cell Rep. 22, 1484–1495 (2018).
Saunderson, S. C., Dunn, A. C., Crocker, P. R. & McLellan, A. D. CD169 mediates the capture of exosomes in spleen and lymph node. Blood 123, 208–216 (2014).
Pucci, F. et al. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352, 242–246 (2016).
Nywening, T. M. et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 17, 651–662 (2016).
Sanford, D. E. et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin. Cancer Res. 19, 3404–3415 (2013).
Zhao, L. et al. Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 57, 829–839 (2013).
Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).
Lim, S. Y., Yuzhalin, A. E., Gordon-Weeks, A. N. & Muschel, R. J. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget 7, 28697–28710 (2016).
Zhang, J., Patel, L. & Pienta, K. J. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 21, 41–48 (2010).
Connolly, K. A. et al. Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 7, 86522–86535 (2016).
Kalbasi, A. et al. Tumor-derived CCL2 mediates resistance to radiotherapy in pancreatic ductal adenocarcinoma. Clin. Cancer Res. 23, 137–148 (2017).
Fridlender, Z. G. et al. CCL2 blockade augments cancer immunotherapy. Cancer Res. 70, 109–118 (2010).
Nywening, T. M. et al. Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut 67, 1112–1123 (2018).
Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014). This study highlights that compensatory pathways are a potential risk and limitation of targeting myeloid cells.
Xu, J. et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 73, 2782–2794 (2013).
Seifert, L. et al. Radiation therapy induces macrophages to suppress T-cell responses against pancreatic tumors in mice. Gastroenterology 150, 1659–1672 (2016).
Wang, Q. et al. Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. Leukemia 32, 176–183 (2018).
Neubert, N. J. et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl Med. 10, eaan3311 (2018).
Mok, S. et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 74, 153–161 (2014). This study shows that targeting macrophages can improve the efficacy of immunotherapy.
Wiehagen, K. R. et al. Combination of CD40 agonism and CSF-1R blockade reconditions tumor-associated macrophages and drives potent antitumor immunity. Cancer Immunol. Res. 5, 1109–1121 (2017). This study finds that blocking CSF1R improves the efficacy of a CD40 agonist, an unexpected finding given that targeting CSF1R is usually associated with reduced macrophage infiltration.
Wainberg, Z. A. et al. First-in-human phase 1 dose escalation and expansion of a novel combination, anti–CSF-1 receptor (cabiralizumab) plus anti–PD-1 (nivolumab), in patients with advanced solid tumors [abstract O42]. J. Immunother. Cancer 5 (Suppl. 3), 89 (2017).
Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668 (2017).
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). This study demonstrates that targeting CSF1R can deplete macrophages in the tumours and metastatic lesions of patients.
Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).
Sanchez-Martin, L. et al. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117, 88–97 (2011).
Wang, S. C., Yu, C. F., Hong, J. H., Tsai, C. S. & Chiang, C. S. Radiation therapy-induced tumor invasiveness is associated with SDF-1-regulated macrophage mobilization and vasculogenesis. PLOS ONE 8, e69182 (2013).
Welford, A. F. et al. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J. Clin. Invest. 121, 1969–1973 (2011).
Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512–526 (2011).
Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017).
Harney, A. S. et al. The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2(Hi) macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol. Cancer Ther. 16, 2486–2501 (2017).
Karagiannis, G. S. et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci. Transl Med. 9, eaan0026 (2017).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Vonderheide, R. H. The immune revolution: a case for priming, not checkpoint. Cancer Cell 33, 563–569 (2018).
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). This is the first clinical study of a CD40 agonist in pancreatic cancer, with complementary murine studies highlighting macrophages as the relevant cellular target.
Byrne, K. T. & Vonderheide, R. H. CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep. 15, 2719–2732 (2016).
Winograd, R. et al. Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol. Res. 3, 399–411 (2015).
Perry, C. J. et al. Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. J. Exp. Med. 215, 877–893 (2018).
Hoves, S. et al. Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. J. Exp. Med. 215, 859–876 (2018).
Guerriero, J. L. et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature 543, 428–432 (2017). This study describes how macrophages can be reprogrammed by targeting their epigenetic state as opposed to utilizing receptor agonists or antagonists.
Schmid, M. C. et al. PI3-kinase gamma promotes Rap1a-mediated activation of myeloid cell integrin alpha4beta1, leading to tumor inflammation and growth. PLOS ONE 8, e60226 (2013).
Sai, J. et al. PI3K inhibition reduces mammary tumor growth and facilitates antitumor immunity and anti-PD1 responses. Clin. Cancer Res. 23, 3371–3384 (2017).
Foubert, P., Kaneda, M. M. & Varner, J. A. PI3Kγ activates integrin α4 and promotes immune suppressive myeloid cell polarization during tumor progression. Cancer Immunol. Res. 5, 957–968 (2017).
De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443–447 (2016).
Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012).
Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nature Med. 21, 1209–1215 (2015).
Xu, M. M. et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein alpha signaling. Immunity 47, 363–373 (2017).
Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).
Hartley, G. P., Chow, L., Ammons, D. T., Wheat, W. H. & Dow, S. W. Programmed cell death ligand 1 (PD-L1) signaling regulates macrophage proliferation and activation. Cancer Immunol. Res. 6, 1260–1273 (2018).
Arlauckas, S. P. et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci. Transl Med. 9, eaal3604 (2017). This study describes how macrophages reduce the efficacy of immune checkpoint blockade through Fc receptor-mediated uptake of the antibody.
DiLillo, D. J. & Ravetch, J. V. Fc-receptor interactions regulate both cytotoxic and immunomodulatory therapeutic antibody effector functions. Cancer Immunol. Res. 3, 704–713 (2015).
Byrne, K. T., Leisenring, N. H., Bajor, D. L. & Vonderheide, R. H. CSF-1R-dependent lethal hepatotoxicity when agonistic CD40 antibody is given before but not after chemotherapy. J. Immunol. 197, 179–187 (2016).
Kitamura, T., Qian, B. Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).
Yang, M., McKay, D., Pollard, J. W. & Lewis, C. E. Diverse functions of macrophages in different tumor microenvironments. Cancer Res. 78, 5492–5503 (2018).