Macrophages as regulators of tumour immunity and immunotherapy

Abstract

Macrophages are critical mediators of tissue homeostasis, with tumours distorting this proclivity to stimulate proliferation, angiogenesis and metastasis. This had led to an interest in targeting macrophages in cancer, and preclinical studies have demonstrated efficacy across therapeutic modalities and tumour types. Much of the observed efficacy can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis. As a result, tumour macrophages display an ability to suppress T cell recruitment and function as well as to regulate other aspects of tumour immunity. With the increasing impact of cancer immunotherapy, macrophage targeting is now being evaluated in this context. Here, we discuss the results of clinical trials and the future of combinatorial immunotherapy.

Figure 1.. Macrophage origin and polarization state.

Tissue macrophages are derived from embryonic or adult progenitor cells under homeostatic conditions, with the relative contribution of these populations varying by tissue. Monocyte-derived cells also contribute to the macrophage population in some tissues, but are mostly associated with a response to inflammatory conditions, including cancer. The combination of their developmental origin and tissue of residence is thought to fine-tune their eventual response to polarizing stimuli.

Figure 2.. Direct and indirect regulation of tumor immunity by TAMs.

A) TAMs can directly inhibit T cell responses through three distinct mechanisms. These include checkpoint engagement via expression of molecules such as PD-L1, production of inhibitory cytokines such as IL-10, and through their metabolic activities, including depletion of metabolites and production of reactive oxygen species (ROS). B) TAMs also inhibit T cell responses indirectly by controlling the immune microenvironment. This includes recruitment of immunosuppressive populations (e.g T_regs) or by inhibiting stimulatory populations (e.g. cDCs). TAMs also blunt T cell recruitment via regulation of vascular structure, and through their ability to exclude T cells from intratumoral regions via regulation of the extracellular matrix (ECM) and the chemokine milieu.

Figure 3.. Cell type versus integrated views on drivers of TAM phenotype.

A) TAM phenotype is driven by a combination of the tumor microenvironment (TME) and the tumor immune microenvironment (TIME). On the left, responses by adaptive and innate immune cells provide cytokines and other factors that regulate macrophage bioactivities. On the right, properties of the tumor microenvironment like hypoxia, fibrosis and cellular stress also tailor the phenotype of TAMs. B) Both immune and non-immune related factors integrate to drive functional or dysfunctional anti-tumor immunity. On the left, the presence of a robust adaptive immune response is concomitant with limited tissue pathology and macrophages programmed to drive inflammation. On the right, tumor hypoxia and fibrosis are integrated with high CAF and immunosuppressive cell infiltration, and macrophages are programmed to drive immune suppression and tissue remodelling, leading to CTL exclusion and/or suppression.