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Myeloid immunosuppression and immune checkpoints in the tumor microenvironment

Cellular & Molecular Immunology volume 17, pages 1–12 (2020)Cite this article

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Abstract

Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages, are critical mediators for sterile and nonsterile inflammation, persistent inflammation, such as that which occurs in cancer, is known to disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment, immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy. Indeed, various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies. These include anti-inflammatory agents, therapeutic blockade of the mobilization and survival of myeloid cells, and immunostimulatory adjuvants. More recently, immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. In this review, we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.

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References

  1. O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).

    Article  PubMed  CAS  Google Scholar 

  2. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor822 stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Junttila, M. R. & de Sauvage, F. J. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501, 346 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Runa, F. et al. Tumor microenvironment heterogeneity: challenges and opportunities. Curr. Mol. Biol. Rep. 3, 218–229 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Nakamura, K. & Smyth, M. J. Targeting cancer-related inflammation in the era of immunotherapy. Immunol. Cell Biol. 95, 325–332 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Coppé, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev. Pathol. 5, 99–118 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Chien, Y. et al. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125–2136 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell. 21, 836–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liu, J. et al. A genetically defined model for human ovarian cancer. Cancer Res. 64, 1655–1663 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Borrello, M. G. et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc. Natl Acad. Sci. USA 102, 14825–14830 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu, S. et al. HER2 overexpression triggers an IL1alpha proinflammatory circuit to drive tumorigenesis and promote chemotherapy resistance. Cancer Res. 78, 2040–2051 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ubertini, V. et al. Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist. Oncogene 34, 2493–2504 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. J. cGAS is essential for cellular senescence. Proc. Natl Acad. Sci. USA 114, E4612–e4620 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Donato, R. et al. Functions of S100 proteins. Curr. Mol. Med. 13, 24–57 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hope, C. et al. TPL2 kinase regulates the inflammatory milieu of the myeloma niche. Blood 123, 3305–3315 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu, Y. et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell. 30, 243–256 (2016).

    Article  PubMed  CAS  Google Scholar 

  22. Su, S. et al. Immune checkpoint inhibition overcomes ADCP-induced immunosuppression by macrophages. Cell 175, 442.e423–457.e423 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Ghaemi-Oskouie, F. & Shi, Y. The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr. Rheumatol. Rep. 13, 160–166 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Di Virgilio, F., Sarti, A. C., Falzoni, S., De Marchi, E. & Adinolfi, E. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat. Rev. Cancer 18, 601–618 (2018).

    Article  PubMed  CAS  Google Scholar 

  25. Karki, R. & Kanneganti, T. D. Diverging inflammasome signals in tumorigenesis and potential targeting. Nat. Rev. Cancer 19, 197–214 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rakoff-Nahoum, S. & Medzhitov, R. Toll-like receptors and cancer. Nat. Rev. Cancer 9, 57 (2008).

    Article  PubMed  CAS  Google Scholar 

  27. Liu, J., Qian, C. & Cao, X. Post-translational modification control of innate immunity. Immunity 45, 15–30 (2016).

    Article  PubMed  CAS  Google Scholar 

  28. Zhang, Q. & Cao, X. Epigenetic regulation of the innate immune response to infection. Nat. Rev. Immunol. 19, 417–432 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Apetoh, L. et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat. Med. 15, 1170 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Sulciner, M. L. et al. Resolvins suppress tumor growth and enhance cancer therapy. J. Exp. Med. 215, 115–140 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Krall J. A., et al. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci. Transl. Med. 10 (2018).

  34. Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Obenauf, A. C. et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520, 368–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Takizawa, H., Boettcher, S. & Manz, M. G. Demand-adapted regulation of early hematopoiesis in infection and inflammation. Blood 119, 2991–3002 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Zhang, P. et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 21, 853–863 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Hirai, H. et al. C/EBPbeta is required for ‘emergency’ granulopoiesis. Nat. Immunol. 7, 732–739 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. 19, 108–119 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lechner, M. G., Liebertz, D. J. & Epstein, A. L. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J. Immunol. 185, 2273–2284 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Marigo, I. et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32, 790–802 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Strauss, L. et al. RORC1 regulates tumor-promoting “emergency” granulo-monocytopoiesis. Cancer Cell. 28, 253–269 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Waight, J. D. et al. Myeloid-derived suppressor cell development is regulated by a STAT/IRF-8 axis. J. Clin. Investig. 123, 4464–4478 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Condamine, T., Mastio, J. & Gabrilovich, D. I. Transcriptional regulation of myeloid-derived suppressor cells. J. Leukoc. Biol. 98, 913–922 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vijayan, D., Young, A., Teng, M. W. L. & Smyth, M. J. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer 17, 709–724 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Corzo, C. A. et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Thevenot, P. T. et al. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity 41, 389–401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bonavita, E. et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160, 700–714 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Reis, E. S., Mastellos, D. C., Ricklin, D., Mantovani, A. & Lambris, J. D. Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18, 5 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 7, 72–85 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Nakamura, K. et al. Dysregulated IL-18 is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. Cancer Cell. 33, 634.e635–648.e635 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Diaz-Montero, C. M. et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol., Immunother. 58, 49–59 (2009).

    Article  CAS  Google Scholar 

  56. Condamine T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immun. 1, aaf8943 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Giese, M. A., Hind, L. E. & Huttenlocher, A. Neutrophil plasticity in the tumor microenvironment. Blood 133, 2159–2167 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shi, J., Hua, L., Harmer, D., Li, P. & Ren, G. Cre driver mice targeting macrophages. Methods Mol. Biol. 1784, 263–275 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hasenberg, A. et al. Catchup: a mouse model for imaging-based tracking and modulation of neutrophil granulocytes. Nat. Methods 12, 445–452 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Movahedi, K. et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 70, 5728–5739 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Szulzewsky, F. et al. Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PloS one 10, e0116644 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Bowman, R. L. et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 17, 2445–2459 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ye, X. Z. et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J. Immunol. 189, 444–453 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Zhu, Y. et al. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47, 323.e326–338.e326 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Loyher, P. L. et al. Macrophages of distinct origins contribute to tumor development in the lung. J. Exp. Med. 215, 2536–2553 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 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 (2019). e510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Radtke, F., Fasnacht, N. & MacDonald, H. R. Notch signaling in the immune system. Immunity 32, 14–27 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Wang, Y. C. et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70, 4840–4849 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Xu, J. et al. NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J. Clin. Investig. 125, 1579–1590 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zheng, S. et al. Inhibition of notch signaling attenuates schistosomiasis hepatic fibrosis via blocking macrophage M2 polarization. PloS one 11, e0166808 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Shen, Q. et al. Notch shapes the innate immunophenotype in breast cancer. Cancer Discov. 7, 1320–1335 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Palaga, T., Wongchana, W. & Kueanjinda, P. Notch signaling in macrophages in the context of cancer immunity. Front. Immunol. 9, 652 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Schmid, M. C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 19, 715–727 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kaneda, M. M. et al. Macrophage PI3Kgamma drives pancreatic ductal adenocarcinoma progression. Cancer Discov. 6, 870–885 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Han, Y. et al. Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression. Cell 173, 634.e612–648.e612 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Zhao, L. et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat. Med. 24, 1536–1544 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nakamura, K. & Smyth, M. J. Aberrant erythropoiesis fuels tumor growth. Cell Res. 28, 611–612 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bosetti, C., Rosato, V., Gallus, S., Cuzick, J. & La Vecchia, C. Aspirin and cancer risk: a quantitative review to 2011. Ann. Oncol. 23, 1403–1415 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Coyle, C. et al. ADD-ASPIRIN: a phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours. Contemp. Clin. Trials 51, 56–64 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hamada, T. et al. Aspirin use and colorectal cancer survival according to tumor CD274 (Programmed cell death 1 ligand 1) expression status. J. Clin. Oncol. 35, 1836–1844 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. New Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lust, J. A. et al. Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin. Proc. 84, 114–122 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ridker, P. M. et al. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Dmitrieva-Posocco, O. et al. Cell-type-specific responses to interleukin-1 control microbial invasion and tumor-elicited inflammation in colorectal cancer. Immunity 50, 166.e167–180.e167 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hong, D. S. et al. MABp1, a first-in-class true human antibody targeting interleukin-1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 15, 656–666 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Turner, D. C. et al. Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance. Clin. Cancer Res. 24, 5841–5849 (2018).

    Article  PubMed  CAS  Google Scholar 

  96. Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50, 778–795 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer 9, 361–371 (2009).

    Article  CAS  PubMed  Google Scholar 

  98. Larkin, J. M. et al. A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma. Br. J. Cancer 103, 1149–1153 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wu, C. et al. Disrupting cytokine signaling in pancreatic cancer: a phase I/II study of etanercept in combination with gemcitabine in patients with advanced disease. Pancreas 42, 813–818 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Madhusudan, S. et al. A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin. Cancer Res. 10, 6528–6534 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Madhusudan, S. et al. Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer. J. Clin. Oncol. 23, 5950–5959 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Haanen, J. et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 28(suppl_4), iv119–iv142 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Perez-Ruiz, E. et al. Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature 569, 428–432 (2019).

    Article  CAS  PubMed  Google Scholar 

  104. Bertrand, F. et al. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat. Commun. 8, 2256 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Vredevoogd, D. W. et al. Augmenting immunotherapy impact by lowering tumor TNF cytotoxicity threshold. Cell 178, 585–599 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Advani, R. H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol. 31, 88–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Sagiv-Barfi, I. et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc. Natl. Acad. Sci. Usa. 112, E966–E972 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Dubovsky, J. A. et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 122, 2539–2549 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Horwood, N. J. et al. Bruton’s tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J. Immunol. 176, 3635–3641 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Ito, M. et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat. Commun. 6, 7360 (2015).

    Article  PubMed  Google Scholar 

  111. Hong D., et al. A phase 1b/2 study of the Bruton tyrosine kinase inhibitor ibrutinib and the PD-L1 inhibitor durvalumab in patients with pretreated solid tumors. Oncology. 11, 102–111 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Molina-Cerrillo, J., Alonso-Gordoa, T., Gajate, P. & Grande, E. Bruton’s tyrosine kinase (BTK) as a promising target in solid tumors. Cancer Treat. Rev. 58, 41–50 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Buchert, M., Burns, C. J. & Ernst, M. Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene 35, 939–951 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Simon N. et al. Tofacitinib enhances delivery of antibody-based therapeutics to tumor cells through modulation of inflammatory cells. JCI Insight. 4, e123281 (2019).

  115. Schonberg, K. et al. JAK inhibition impairs NK cell function in myeloproliferative neoplasms. Cancer Res. 75, 2187–2199 (2015).

    Article  PubMed  CAS  Google Scholar 

  116. Bottos, A. et al. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models. Nat. Commun. 7, 12258 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Vasquez-Dunddel, D. et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J. Clin. Investig. 123, 1580–1589 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wong, A. L. A. et al. Do STAT3 inhibitors have potential in the future for cancer therapy? Expert Opin. Investig. Drugs 26, 883–887 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  CAS  PubMed  Google Scholar 

  121. Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Loberg, R. D. et al. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res. 67, 9417–9424 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Ma, Y. et al. CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy. Cancer Res. 74, 436–445 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Pienta, K. J. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Investig. N. Drugs 31, 760–768 (2013).

    Article  CAS  Google Scholar 

  126. Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Lyons, Y. A. et al. Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy. Oncotarget 8, 96496–96505 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Tap, W. D. et al. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor. N. Engl. J. Med. 373, 428–437 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Richardsen, E., Uglehus, R. D., Johnsen, S. H. & Busund, L. T. Macrophage-colony stimulating factor (CSF1) predicts breast cancer progression and mortality. Anticancer Res. 35, 865–874 (2015).

    PubMed  Google Scholar 

  132. Pettenati, C. & Ingersoll, M. A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 15, 615–625 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Takeda, Y. et al. A TLR3-specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep. 19, 1874–1887 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. Ramanjulu, J. M. et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature 564, 439–443 (2018).

    Article  CAS  PubMed  Google Scholar 

  136. Vonderheide, R. H. & Glennie, M. J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035–1043 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Dahan, R. et al. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective FcgammaR engagement. Cancer Cell. 29, 820–831 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Knorr, D. A., Dahan, R. & Ravetch, J. V. Toxicity of an Fc-engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable antitumor immunity. Proc. Natl Acad. Sci. USA 115, 11048–11053 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. LaRocca, C. J. & Warner, S. G. Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials. Clin. Transl. Med. 7, 35 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Denton, N. L., Chen, C. Y., Scott, T. R. & Cripe, T. P. Tumor-associated macrophages in oncolytic virotherapy: friend or foe? Biomedicines 4, 3 (2016).

    Article  CAS  Google Scholar 

  141. Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069 (2018).

    Article  PubMed  Google Scholar 

  142. Lin, H. et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J. Clin. Investig. 128, 805–815 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Gandini, S., Massi, D. & Mandala, M. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis. Crit. Rev. Oncol./Hematol. 100, 88–98 (2016).

    Article  Google Scholar 

  145. Yao, S. et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood 113, 5811–5818 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bally, A. P. et al. NF-kappaB regulates PD-1 expression in macrophages. J. Immunol. 194, 4545–4554 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. Martinez, G. J. et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42, 265–278 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Gordon, S. R. et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 545, 495–499 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhao, Y. et al. Antigen-presenting cell-intrinsic PD-1 neutralizes PD-L1 in cis to attenuate PD-1 signaling in T cells. Cell Rep. 24, 379.e376–390.e376 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sugiura, D. et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science 364, 558–566 (2019).

    Article  CAS  PubMed  Google Scholar 

  152. Chaudhri, A. et al. PD-L1 binds to B7-1 only in cis on the same cell surface. Cancer Immunol. Res. 6, 921–929 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Monney, L. et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Sanchez-Fueyo, A. et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. 4, 1093–1101 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245–1252 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Anderson, A. C. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol. Res. 2, 393–398 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Nakayama, M. et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113, 3821–3830 (2009).

    Article  CAS  PubMed  Google Scholar 

  159. Chiba, S. et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13, 832–842 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. de Mingo Pulido, Á. et al. TIM-3 regulates CD103+ dendritic cell function and response to chemotherapy in breast cancer. Cancer Cell. 33, 60.e66–74.e66 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Heusschen, R., Griffioen, A. W. & Thijssen, V. L. Galectin-9 in tumor biology: a jack of multiple trades. Biochim. Biophys. Acta 1836, 177–185 (2013).

    CAS  PubMed  Google Scholar 

  162. Kikushige, Y. et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell. Stem Cell. 7, 708–717 (2010).

    Article  CAS  PubMed  Google Scholar 

  163. Kikushige, Y. et al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell. Stem Cell. 17, 341–352 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Kuroki, K., Furukawa, A. & Maenaka, K. Molecular recognition of paired receptors in the immune system. Front. Microbiol. 3, 429 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Hayashi, A. et al. Positive regulation of phagocytosis by SIRPbeta and its signaling mechanism in macrophages. J. Biol. Chem. 279, 29450–29460 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Barclay, A. N. & Brown, M. H. The SIRP family of receptors and immune regulation. Nat. Rev. Immunol. 6, 457–464 (2006).

    Article  CAS  PubMed  Google Scholar 

  167. Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Yanagita, T. et al. Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy. JCI Insight 2, e89140 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Li, Y. et al. Overexpression of CD47 predicts poor prognosis and promotes cancer cell invasion in high-grade serous ovarian carcinoma. Am. J. Transl. Res. 9, 2901–2910 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Advani, R. et al. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma. N. Engl. J. Med. 379, 1711–1721 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Burshtyn, D. N. & Morcos, C. The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors. J. Immunol. 196, 947–955 (2016).

    Article  CAS  PubMed  Google Scholar 

  174. Held, W. & Mariuzza, R. A. Cis interactions of immunoreceptors with MHC and non-MHC ligands. Nat. Rev. Immunol. 8, 269–278 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Takai, T. Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology 115, 433–440 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Endo, S., Sakamoto, Y., Kobayashi, E., Nakamura, A. & Takai, T. Regulation of cytotoxic T lymphocyte triggering by PIR-B on dendritic cells. Proc. Natl Acad. Sci. USA 105, 14515–14520 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Ma, G. et al. Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells. Immunity 34, 385–395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. van der Touw, W., Chen, H. M., Pan, P. Y. & Chen, S. H. LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol. Immunother. 66, 1079–1087 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Chen, H. M. et al. Blocking immunoinhibitory receptor LILRB2 reprograms tumor-associated myeloid cells and promotes antitumor immunity. J. Clin. Investig. 128, 5647–5662 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Barkal, A. A. et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19, 76–84 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Asano, K. et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34, 85–95 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Chen, G. Y., Tang, J., Zheng, P. & Liu, Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323, 1722–1725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Chen, G. Y. et al. Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction. Nat. Biotechnol. 29, 428–435 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Macauley, M. S., Crocker, P. R. & Paulson, J. C. Siglec-mediated regulation of immune cell function in disease. Nat. Rev. Immunol. 14, 653–666 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kristiansen, G. et al. CD24 is an independent prognostic marker of survival in nonsmall cell lung cancer patients. Br. J. Cancer 88, 231–236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Kristiansen, G. et al. CD24 expression is a new prognostic marker in breast cancer. Clin. Cancer Res. 9, 4906–4913 (2003).

    CAS  PubMed  Google Scholar 

  188. Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Fang, X., Zheng, P., Tang, J. & Liu, Y. CD24: from A to Z. Cell. Mol. Immunol. 7, 100 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Goldstein, J. L., Ho, Y. K., Basu, S. K. & Brown, M. S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc. Natl Acad. Sci. USA 76, 333–337 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Canton, J., Neculai, D. & Grinstein, S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 13, 621–634 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Roszer, T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm. 2015, 816460 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Yu, X., Guo, C., Fisher, P. B., Subjeck, J. R. & Wang, X. Y. Scavenger receptors: emerging roles in cancer biology and immunology. Adv. Cancer Res. 128, 309–364 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Shigeoka, M. et al. Tumor associated macrophage expressing CD204 is associated with tumor aggressiveness of esophageal squamous cell carcinoma. Cancer Sci. 104, 1112–1119 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hirayama, S. et al. Prognostic impact of CD204-positive macrophages in lung squamous cell carcinoma: possible contribution of Cd204-positive macrophages to the tumor-promoting microenvironment. J. Thorac. Oncol. 7, 1790–1797 (2012).

    Article  CAS  PubMed  Google Scholar 

  197. Wang, X. Y., Facciponte, J., Chen, X., Subjeck, J. R. & Repasky, E. A. Scavenger receptor-A negatively regulates antitumor immunity. Cancer Res. 67, 4996–5002 (2007).

    Article  CAS  PubMed  Google Scholar 

  198. Neyen, C. et al. Macrophage scavenger receptor a promotes tumor progression in murine models of ovarian and pancreatic cancer. J. Immunol. 190, 3798–3805 (2013).

    Article  CAS  PubMed  Google Scholar 

  199. Arredouani, M. S. Is the scavenger receptor MARCO a new immune checkpoint? Oncoimmunology 3, e955709 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Mukhopadhyay, S. et al. SR-A/MARCO-mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens. Blood 117, 1319–1328 (2011).

    Article  CAS  PubMed  Google Scholar 

  201. Komine, H., Kuhn, L., Matsushita, N., Mule, J. J. & Pilon-Thomas, S. Examination of MARCO activity on dendritic cell phenotype and function using a gene knockout mouse. PloS One 8, e67795 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Georgoudaki, A. M. et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 15, 2000–2011 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. Kzhyshkowska, J., Gratchev, A. & Goerdt, S. Stabilin-1, a homeostatic scavenger receptor with multiple functions. J. Cell. Mol. Med. 10, 635–649 (2006).

    Article  CAS  PubMed  Google Scholar 

  204. David, C. et al. Stabilin-1 expression in tumor associated macrophages. Brain Res. 1481, 71–78 (2012).

    Article  CAS  PubMed  Google Scholar 

  205. Palani, S., Elima, K., Ekholm, E., Jalkanen, S. & Salmi, M. Monocyte Stabilin-1 suppresses the activation of Th1 lymphocytes. J. Immunol. 196, 115–123 (2016).

    Article  CAS  PubMed  Google Scholar 

  206. Viitala, M. et al. Immunotherapeutic blockade of macrophage Clever-1 reactivates the CD8+ T-cell response against immunosuppressive tumors. Clin. Cancer Res. 25, 3289–3303 (2019).

    Article  PubMed  CAS  Google Scholar 

  207. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Netea-Maier, R. T., Smit, J. W. A. & Netea, M. G. Metabolic changes in tumor cells and tumor-associated macrophages: a mutual relationship. Cancer Lett. 413, 102–109 (2018).

    Article  CAS  PubMed  Google Scholar 

  209. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Forssell, J. et al. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin. Cancer Res. 13, 1472–1479 (2007).

    Article  CAS  PubMed  Google Scholar 

  211. Ponzetta, A. et al. Neutrophils driving unconventional T cells mediate resistance against murine sarcomas and selected human tumors. Cell 178, 346–360 (2019). e324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Peng, D. et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 76, 3156–3165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Sainz, B. Jr., Martin, B., Tatari, M., Heeschen, C. & Guerra, S. ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Res. 74, 7309–7320 (2014).

    Article  CAS  PubMed  Google Scholar 

  214. Wan, S. et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404 (2014).

    Article  CAS  PubMed  Google Scholar 

  215. Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Sadaat, M. & Jang, S. Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report. J. Immunother. Cancer 6, 49 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Liu, J., Blake, S. J., Smyth, M. J. & Teng, M. W. Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. Clin. Transl. Immunol. 3, e22 (2014).

    Article  CAS  Google Scholar 

  218. Song, M., Liu, T., Shi, C., Zhang, X. & Chen, X. Bioconjugated manganese dioxide nanoparticles enhance chemotherapy response by priming tumor-associated macrophages toward M1-like phenotype and attenuating tumor hypoxia. ACS nano. 10, 633–647 (2016).

    Article  CAS  PubMed  Google Scholar 

  219. Agostinis, P. et al. Photodynamic therapy of cancer: an update. CA: a Cancer J. Clinicians. 61, 250–281 (2011).

    Google Scholar 

  220. Morrissey M. A., et al. Chimeric antigen receptors that trigger phagocytosis. eLife. 7, pii: e36688 (2018).

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Acknowledgements

We appreciate Dr. Antonio Sica and Professor Alberto Mantovani for their critical reading and suggestions for this review. We also wish to thank members of our laboratory for helpful suggestions. K.N. was supported by a Naito Foundation and a NHMRC Project Grant (1174363). M.J.S. was supported by a National Health and Medical Research Council (NH&MRC) Senior Principal Research Fellowship (1078671) and Program Grant (1132519). K.N. and M.J.S were recipients of a Leukaemia Foundation of Australia SERP grant.

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  1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, 4006, QLD, Australia

    Kyohei Nakamura & Mark J. Smyth

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M.J.S has research agreements with Bristol Myers Squibb and Tizona Therapeutics and is a member of the Scientific Advisory Board (SAB) for Tizona Therapeutics and Compass Therapeutics.

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Nakamura, K., Smyth, M.J. Myeloid immunosuppression and immune checkpoints in the tumor microenvironment. Cell Mol Immunol 17, 1–12 (2020). https://doi.org/10.1038/s41423-019-0306-1

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