Protumor Activities of the Immune Response: Insights in the Mechanisms of Immunological Shift, Oncotraining, and Oncopromotion
Figure 2
Pro-tumoral activities of the immune system. (a) Soluble factors secreted by tumor and immune cells create a microenvironment in which arriving and local immune cells are (i) inactivated creating immunosuppressive conditions, (ii) maintaining inflammation, and/or (iii) switched from anti- to pro-tumoral activities. Tregs, M2 macrophages, N2 neutrophils, and MDSCs are among the most important immunosuppressive populations and IL-10 and TGF-β the main cytokines contributing to this microenvironment. A chronic inflammatory microenvironment contributes to oncogenesis and tumor growth through secretion of mutagenic (e.g., ROS) or inflammatory molecules (e.g., COX-2). Almost all innate immune populations contribute to inflammation plus Th17 and Th2 T and B cells. The anti- to pro-tumoral switch refers to a mechanism in which the tumor microenvironment reprograms or trains the immune cells to perform activities more in tune with the tumor needs (oncopromotion). Polarization to M2 macrophages and N2 neutrophils are perhaps the most studied examples of this process. Among the important molecules for inflammation, oncotraining, and oncopromotion are G-CSF, GM-CSF, and M-CSF (for immune cell recruitment), VEGF (for angiogenesis), proteases (matrix degradation), and TGF-β (for EMT). Overall this mechanism contributes to tumor growth, invasion, formation of distant pro-tumoral niches and metastasis (oncopromotion). (b) Intrinsic changes in tumor cells in response to the tumor microenvironment. Signaling from receptors to growth factors, interleukins and other inflammatory molecules activate many pathways. Among the most important are MAPKs and STATs triggering proliferation (e.g., in response to FGF, EGF, HGF and some cytokines), NFκB and PI3K triggering cell survival (e.g., in response to interleukins). Also, one of the most critical mechanisms contributing to tumor malignancy is the transition from epithelial to a more mobile mesenchymal phenotype (EMT) (see text for a detailed explanation).
