Handbook of Targeted Cancer Therapy and Immunotherapy

111 action of these therapies is likely far more complex as both PD-1 and its ligands are expressed on several different cell types (32). Likewise, other inhibitory immune checkpoints such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) emerge more proximal to T-cell priming (33). Thus, the expression of PD-1, CTLA-4, and numerous other inhibitory receptors on T cells can enable functional impairment of antitumor immunity, and do so via distinct mechanisms (Figure 11.2). Importantly, multiple inhibitory immune checkpoint receptors have been characterized on the surface of T cells beyond PD-1, and these are often concurrently expressed, emphasizing their redundancy in function to sus tain an immunologic advantage to tumors (34). T-Cell Extrinsic Mechanisms Hinder Immunity against GI Malignancy Complementing these hard-wired, T-cell-intrinsic suppressive mechanisms are a host of other cell types that limit antitumor immune responses via forces that are “extrinsic” to the T cells themselves. As discussed earlier, the landscape of immune cells populating GI tumors is dic tated by cytokine and chemokine mediators. The net result is a limited number of both effector T cells, as well as cells with capacity to present tumor antigen and mount productive immune responses (20). One relevant example of this is recent evidence for IL-6-dependent apoptosis of type I dendritic cells (DC1) in pancreatic tumors (35). Importantly, this likely occurs early during the course of disease progression, even at the stage of PanIN lesions, further contributing to inadequate T-cell responses against these tumors. Myeloid cells including MDSC and TAM are prominent cellular components across the spectrum of GI tumors and suppress T-cell-mediated antitumor immune responses via several concurrent mechanisms. These include secretion of im mune modulatory cytokines including TGF- β that directly limits cytotoxic capacity of T and NK cells, IL-10 that limits DC maturation and IL-6 that can promote MDSC expansion, and skewed T-cell profiles toward either T reg or Th17 phenotypes, depending on the other cytokines present (Figure 11.3) (36,37).

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