Figure 4 Macrophage-targeting antitumour treatment approaches

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Figure 4 Macrophage-targeting antitumour treatment approaches Figure 4 | Macrophage-targeting antitumour treatment approaches. Macrophage-centred therapeutic approaches are aimed at either activating the antitumour activity, or inhibiting the recruitment and tumour-promoting functions of this cell type. a | The concerted action of microbial moieties (acting via Toll-like receptors; TLRs) and IFNγ induces M1-like functional polarization of macrophages (Box 1), and can activate these cells to kill tumour cells either directly, or indirectly by promoting adaptive immune responses. Macrophage-mediated antibody-dependent cellular cytotoxicity (ADCC) is often integral to the antitumour effect of therapeutic antibodies. Activation of this process involves recognition of the therapeutic antibodies by Fc receptors (FcRs) expressed on the surface of macrophages. Tumour cells can express CD47, a 'don't eat me' signal that, via interaction with SIRPα prevents phagocytosis by macrophages. Thus, interference with the SIRPα–CD47 pathway — for example, using antagonistic antibodies — can activate macrophage-mediated antibody-dependent cellular phagocytosis (ADCP), which subsequently results in functional skewing of macrophages in an M1 direction that is associated with antitumour activity. In addition, activation of the co-stimulatory receptor CD40 using an anti-CD40 antibody has been demonstrated to re-educate immunosuppressive, tumour-promoting, M2-like macrophages in the tumour microenvironment to an M1-like phenotype, leading to re-establishment of tumour immune surveillance. b | Monocyte-attracting molecules, including chemokines (such as CCL2 and CCL5), cytokines (for example, VEGF and CSF-1), and complement mediators (C5a) are involved in the recruitment of tumour-associated macrophage (TAM)-precursors to tumours. Inhibitors of these chemoattractants or their receptors with specific monoclonal antibodies (such as the anti-CCL2 antibody carlumab, or the anti-CSF-1 antibody emactuzumab), or antagonists (for example, the CCR5-antagonist maraviroc) can prevent macrophage accumulation within the tumour microenvironment, thereby reducing tumour growth and dissemination. CSF-1 antagonists also have the potential to inhibit macrophage survival. The DNA-binding agent trabectedin, an approved anticancer therapy, activates caspase-dependent apoptosis selectively in cells of the monocyte lineage that express TRAIL receptors (TRAIL-R), thus causing partial depletion of both circulating monocytes and TAMs. The protective function of nonsteroidal anti-inflammatory drugs (NSAIDS), particularly aspirin, against the development of primary cancer and metastases is related to inhibited synthesis of prostaglandins, which have immunosuppressive properties; TAM contribute to suppression of adaptive immunity via expression of cyclooxygenases (COX-1/2) involved in prostaglandin production, as well as other proteins with immunosuppressive functions, including indoleamine-pyrrole 2,3-dioxygenase (IDO), TGFβ, and IL-10. Moreover, TAMs express ligands, such PD-L1, PD-L2, B7-H4, and VISTA, that trigger inhibitory immune-checkpoint receptors. HO, haeme oxygenase. Mantovani, A. et al. (2017) Tumour-associated macrophages as treatment targets in oncology Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.217