Handbook of Targeted Cancer Therapy and Immunotherapy
110 Redundant Mechanisms of Immune Suppression Are Evident in GI Tumors In general, many GI tumors are what is considered “immunologically cold,” meaning they lack abundant effector T-cell infiltrates. This is likely due to multiple factors, including but not limited to poor availability of neoantigens in tumors, inadequate chemokine gradi ents to enable their trafficking, or T-cell apoptosis upon entry into the hostile TME (20). Of ten, effector T cells are sequestered in regions distant from tumor cells, and those T cells that do gain access display phenotypic properties consistent with exhaustion. Other data indicate T-cell subsets including T regs or Th17 cells are present in these tumors, and may contribute to the impaired antitumor immune response. In contrast, myeloid cells and macrophages are major components within GI malignancies (28–30). These cells may be derived from tissue resident populations or alternatively are home to the microenvironment via the circulation. Taken together, the cellular composition of GI tumors enables multiple redundant mechanisms that inhibit productive antitumor immune responses. In general terms, mechanisms of limiting antitumor T-cell-mediated immune responses can be subdivided into two categories: (1) mech anisms that are intrinsic to the T cell itself (i.e., T-cell intrinsic) or (2) those mediated extrinsic soluble or cellular factors in the environment that feed back to limit T-cell function (i.e., T-cell extrinsic). T-Cell Intrinsic Mechanisms Can Limit Antitumor Immune Responses The most notable T-cell intrinsic mechanisms of suppressed antitumor immune responses are exemplified by inhibitory immune checkpoint receptors present on the surface on immune cell populations including T cells. Indeed, a wealth of knowledge is now available regarding the mechanism by which targeting the inhibitory programmed cell death protein 1 (PD-1) receptor and its interactions with ligands programmed death ligand-1 (PD-L1) and PD-L2 can perpetuate exhaustion phenotypes in T cells upon chronic antigen stimulation, thereby influencing antitumor immune response (reviewed in Pauken et al. [31]). The mechanism of
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