Fig. 2. The immunosuppressive properties of tumor-associated macrophages (TAMs) in the tumor immune microenvironment (TIME).

Numerous tumor-derived factors, some of which have been shown to activate Nrf2, induce the development of the TAMs into ‘alternatively activated M2’ phenotype, exhibiting immunosuppressive and pro-invasive characteristics. These M2-like TAMs promote immune suppression in various ways, including induction of regulatory T (T_reg) cells (through secretion of IL-10 and TGF-β), inhibition of T-cell activation and proliferation, reduction of the activity of natural killer (NK) cells and CD8⁺ T cells, and promoting T-cell apoptosis. Increased levels of the MHC class I antigens HLA-G, HLA-E and prostaglandin E₂ (PGE₂) in TAMs may affect the activity of lymphokine-activated killer (LAK) cells, NK cells and cytotoxic T cells (CTLs), and inhibit the proliferation of T cells further. Increased levels of IL-6 and IL-10 and decreased levels of the MHC class II cell surface receptor HLA-DR, co-stimulatory factors, such as CD40, CD80, CD86, and pro-inflammatory cytokines, as well as diminished phagocytic activity of TAMs also contribute to T-cell inhibition. Reduced expression of CD40, CD80 and CD86 promotes T cell anergy and apoptosis. Additionally, TAMs induce differentiation of MDSCs into M2-like macrophages and increase recruitment of cancer-associated fibroblasts (CAFs). MDSC, myeloid-derived suppressor cell; IL-10, interleukin 10; TGF-β, transforming growth factor β; MHCII, MHC class II. Adapted from Wurdinger et al. (2014).