Handbook of Targeted Cancer Therapy and Immunotherapy

106 Introduction Gastrointestinal (GI) tumors harbor a series of distinct immunologic features and are comprised of heterogeneous immune cell populations. The origins of many GI malig nancies are closely related to inflammatory pathology, which may influence the landscape of cyto kines, chemokines, and cellular constituents of these tumors. The failure of both endogenous and immunotherapy-induced antitumor immune responses across a range of GI malignancies is mul tifactorial. Several factors intrinsic to T cells themselves, such as inhibitory immune checkpoint receptors, or extrinsic to the T cells, including cytokines, chemokines, or suppressive cell types, comprise a redundant network that limits antitumor immunity. This dominant, suppressive im mune phenotype can be characterized by canonical skewing of cytokine and chemokine profiles, paired with limited effector T-cell infiltration and a predominance of myeloid-lineage cells. Finally, the complexity of the microenvironment within GI tumors is also reflected in heterogeneous cancer-associated fibroblast (CAF) populations that facilitate cross-talk with both tumor and im mune cells to regulate disease progression. This chapter provides an overview of key immunologic features of GI malignancies and provides a perspective related to priorities for future multidisci plinary research to advance the field. The Microenvironment of GI Tumors Harbors Cellular Complexity Malignancy can develop across multiple organ sites within the GI system, leading to aggressive tumors, many of which harbor key immunologic features. Complex cellular interactions with the immune system influence the course of disease and the response to immunotherapy (1). Thus, there is clinical importance in understanding the biology behind why these tumors are inherently non responsive to immunotherapy. Ultimately this could enable innovative treatment approaches for overcoming barriers to efficacy. One notable feature across GI cancer types is the striking cellular heterogeneity that exists within the tumor microenvironment (TME). It is now appreciated that a diverse array of cell populations can cooperate with transformed cells, further amplifying their ag gressive behavior or shielding them from elimination by endogenous immune cells (Figure 11.1) (2). Key cellular components of the TME encompass vasculature, such as pericytes or endothelial cells,

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