Expanding the Scope of Immunotherapy in Colorectal Cancer: Current Clinical Approaches and Future Directions

Figure 2

dMMR-MSI-H and pMMR-MSI-L CRCs have distinct tumor microenvironments. (a) dMMR-MSI-H tumor cells are characterized by their high rates of mutations that result in the presentation of mutated peptides on their MHC class I molecules. These are in turn recognized as foreign neoantigens by immune cells, resulting in high densities of cytotoxic CD8+ T-cell and helper 1 CD4+ T-cell infiltration and elevated levels of IFN-gamma secretion. Tumor growth and progression is also influenced by the abundant tumor-associated macrophages present in the tumor microenvironment. As a means to evade the immune-mediated killing, dMMR-MSI-H tumor cells tend to upregulate the expression of T-cell inhibitory ligands, including B7 (CD80, CD86) and PDL1, which bind to the co-inhibitory CTLA4 and PD1 receptors. (b) By contrast, pMMR-MSI-L tumors generate wild-type peptides that are not immune-stimulatory and are thus characterized by much lower density of TILs.

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