Figure 1.

Immunosuppressive tumor microenvironment and antigen loss mediate tumor escape. During the elimination phase immune effector cells such as CTL’s and NK cells with the help of dendritic and CD4+ T-cells are able to recognize and eliminate tumor cells. This killing relies on stress ligands such as NKG2D and recognition of TAA’s in the TCR-MHC complex. As a result of tumor heterogeneity, tumor cells which are less immunogenic or have up-regulated immunosuppressive factors are selected for. These cells are able to subvert the immune response and escape immune surveillance. Tumor cells can secrete cytokines that recruit suppressive cells such as regulatory T (T_reg) cells, immature myeloid cells [including immature dendritic cells (iDC) and myeloid-derived suppressor cells (MDSC)], and M2 macrophages. iDC can cause T-cell anergy due to lack of co-stimulatory molecules. M2 macrophages and MDSC inhibit T-cell responses through a variety of mechanisms, including nutrient sequestration via arginase, reactive oxygen species (ROS) generation, nitric oxide (NO), as well as interference with trafficking into the tumor site. Immunosuppressive cytokines and the up-regulation of immunosuppressive enzymes [like indolamine-2,3-dioxygenase (IDO) and arginase] that catabolize essential nutrients required for effector cell activation and also produce immunosuppressive catabolites, contribute to a microenvironment where immune responses are difficult to instigate and sustain. Furthermore tumor cells will down-regulate MHC molecules, loose expression of antigenic molecules, and up-regulate inhibitory molecules such as PD-L1.