Tumour-associated macrophages as treatment targets in oncology

Abstract

Macrophages are crucial drivers of tumour-promoting inflammation. Tumour-associated macrophages (TAMs) contribute to tumour progression at different levels: by promoting genetic instability, nurturing cancer stem cells, supporting metastasis, and taming protective adaptive immunity. TAMs can exert a dual, yin-yang influence on the effectiveness of cytoreductive therapies (chemotherapy and radiotherapy), either antagonizing the antitumour activity of these treatments by orchestrating a tumour-promoting, tissue-repair response or, instead, enhancing the overall antineoplastic effect. TAMs express molecular triggers of checkpoint proteins that regulate T-cell activation, and are targets of certain checkpoint-blockade immunotherapies. Other macrophage-centred approaches to anticancer therapy are under investigation, and include: inhibition of macrophage recruitment to, and/or survival in, tumours; functional re-education of TAMs to an antitumour, 'M1-like' mode; and tumour-targeting monoclonal antibodies that elicit macrophage-mediated extracellular killing, or phagocytosis and intracellular destruction of cancer cells. The evidence supporting these strategies is reviewed herein. We surmise that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapy.

Figure 1. A schematic representation of the role of tumor-associated macrophages in tumor progression.

Panel A. Monocytes and MoMDSC (see Box 1) are recruited in tumors in response to diverse chemoattractants including CSF1, chemokines and complement components. In tumors, monocytes differentiate into macrophages (Tumor-associated macrophages, TAM). In some tumors, in situ proliferation may occur and local tissue resident macrophages of embryonic origin may contribute to TAM. Signals in the tumor microenvironment skew the function of TAM. Panel B. Pathways and molecules polarizing TAM differ in different tumors. These include: IL-4 and IL-13 derived from TH2 cells, eosinophils (Eos) and basophils (Bas); cytokines and metabolites from tumor cells; antibodies (Ab) from B cells and immune complexes (Ic); stromal cell-derived factors (IL-1, LT). Panel C. TAM affect virtually all aspects of tumor cell biology, including provision of a niche for cancer stem cells (CSC); angiogenesis; epithelial to mesenchymal transition (EMT); invasion and metastasis; proliferation; genetic instability.

Figure 2. Bimodal function of TAM in response to chemotherapy and radiotherapy.

Macrophages orchestrate immune responses that can either hamper (left) or foster (right) the effectiveness of conventional anticancer strategies. On the left: cytotoxic agents enhance tumor infiltration by immunosuppressive macrophages, which activate chemoprotective T cells and tame adaptive immune responses; chemotherapy or radiotherapy-induced tissue damage triggers the recruitment of immunosuppressive myeloid cells, which orchestrate a misdirected tissue-repair response, promoting tumor growth and revascularization; macrophages, an essential component of tissue stem cell niches, can protect CSC against cytotoxicity. On the right: selected chemotherapeutic agents (e.g Doxorubicin) increase the immunogenicity of malignant cells (immunogenic cell death), which stimulate myeloid cells to differentiate into antigen presenting cells and trigger effective adaptive immune responses; anticancer agents like Gemcitabine can directly skew macrophage effector functions towards an antitumor mode and increase their cytotoxicity, resulting into a favorable synergism; neoadjuvants low-dose γ-irradiation set macrophage functions in an antitumor mode, promoting regression at sites distant from irradiated lesions (abscopal effect). CSC: cancer stem cells.

Figure 3. Schematic representation of strategies targeting macrophages in tumor settings.

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.