Macrophage-centered therapeutic approaches are aimed either at activating their
antitumor activity (Panel A) or inhibiting their recruitment and functions
related to tumor promotion (panel B).
Panel A: the concerted action of microbial moieties (acting via
TLRs) and IFNγ induces M1-like functional polarization and can activate
macrophage killing of tumor cells; macrophage-mediated antibody-dependent
cytotoxicity (ADCC) can mediate the therapeutic effect of therapeutic
antibodies; interference with the SIRPα-CD47 pathway activates
macrophage-mediated antibody-dependent phagocytosis (ADCP) and results in
functional skewing of macrophages in an M1 direction and antitumor activity; an
anti-CD40 antibody re-educates M2-like macrophages in the tumor
microenvironment, leading to re-establishment of tumor immune surveillance.
Panel B: Inhibition of monocyte-attracting molecules, including
chemokines (e.g CCL2, CCL5), VEGF, CSF-1 and complement mediators (C5a) with
specific monoclonal antibodies (e.g. carlumab, emactuzumab) or antagonists (e.g.
maraviroc) prevent macrophage recruitment to the tumor microenvironment,
reducing tumor growth and dissemination; inhibitors of CSF-1 have also the
potential to inhibit macrophage survival; Trabectedin activates a
caspase-dependent pathway of apoptosis, selectively in cells of the monocyte
lineage, causing a partial depletion of circulating monocytes and TAM; the
protective function of NAIDS, aspirin in particular, against primary cancer and
metastasis relies on the inhibition of prostaglandin production, which have
immunosuppressive properties; TAM contribute to suppression of adaptive immunity
by expression of immunosuppressive molecules, such as IDO, cyclooxygenases
(COX1,2), TGFβ and IL-10. Moreover, TAM express triggers of checkpoint
blockade, such PD-L1, PD-L2, B7H4 and VISTA.
TLR: Toll-like receptors; IFNRα: interferon receptor alpha; FcR: Fc
receptor, mAb: monoclonal antibody; VEGF: vascular endothelial growth factor;
CSF-1: colony-stimulating factor; NAIDS: nonsteroidal anti-inflammatory drugs;
IDO: indoleamine 2,3 dioxygenase; TGFβ: transforming growth factor
β; IL-10: interleukin 10.