Handbook of Targeted Cancer Therapy and Immunotherapy

114 In a similar manner, B cells have been noted to secrete the cytokine IL-35 in sev eral GI malignancies, resulting in exclusion of CD8 + T cells from the tumor (38,39). In addition to cytokine mediators, suppressive immune cells can serve as potent regulators of metabolic features within the TME. There are many examples of this (reviewed in Lyssiotis et al. [40]) including lactate, indoleamine-pyrrole 2,3-dioxygenase-me diated tryptophan catabolism, production of arginase and cysteine deprivation, among others (41). More recently, attention has turned to immune cells with more innate properties including gamma delta T cells or innate lymphoid cells (ILC2) as additional components of the suppres sive TME (42,43). The sheer redundancy in cellular and soluble factors likely emphasizes the need for combination therapy approaches to derive the best chance at success in aggressive GI malignancies (44). CAFs: At the Crossroads of Communication between Tumor and Immune Cells A deep appreciation for the role of CAFs in communicating with both the tumor and immune cells has more recently emerged. These cells reside across GI tumors of varied anatomic origin and a lit any of publications have established their contributions to both fibrosis and immune suppression. However, it is important to note that many mechanistic assumptions related to CAF populations are derived from studies performed in pancreatic cancer. CAF populations have certainly been noted across other GI tumor types, including cholangiocarcinoma, colorectal cancer, hepatocel lular carcinoma, and several others (45,46). The prevalence of these cells across disease settings emphasizes their importance in establishing and maintaining at least some common aspects of GI tumors, regardless of histology. Recent studies provide evidence for heterogeneity in inflammatory fibroblasts residing in tumor stroma (47–49). These data suggest that subpopulations of CAF can be defined based on alpha-smooth muscle actin ( α -SMA) and IL-6, along with other markers. The topic of stromal components as promoting or inhibiting PDAC has definitely been a source of some controversy (50–52). For example, genetic ablation of SMA + stromal cells accelerated metastasis in a murine model of PDAC driven by oncogenic Kras (53). However, in this same tumor model, immunotherapy with anti-CTLA-4 antibody (Ab) was more effective when mice lacked SMA + cells

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