Handbook of Targeted Cancer Therapy and Immunotherapy

115 (53). Other animal studies have shown that fibroblast activation protein (FAP)-positive populations of CAF function to maintain stroma and suppress antitumor immune re sponses (24,54,55). Aligned with the observations that cytokine profiles shape the immune cells pres ent with tumors are data demonstrating another critical role for cytokines in regulating CAF plas ticity. Using a series of organoid and other experimental models, Biffi et al. demonstrated that IL-1 α and likely other factors from primary PDAC tumors promote an inflammatory CAF (iCAF) phe notype, whereas exposure of these same cells to TGF- β preferentially expands myofibroblast-like CAF (myCAFs) (56). iCAFs are defined via high IL-6 expression and are usually localized to fibrotic regions, more distant from adenocarcinoma in primary tumors. These iCAF cells promote immune suppression changes in the TME via IL-6 production (47,56). In contrast, myCAFs produce less IL-6 but express high levels of the α -SMA marker, and reside closer in proximity to malignant cells (47,56). Other heterogeneous CAF subsets have been assigned specialized functions, including the CD74 + MHCII + CAFs capable of presenting antigen to CD4 + T cells (57) or others expressing markers such as CD10 or CD105 (58,59). The advent of single-cell profiling technologies has also enabled dis covery of other relevant targets on CAF (e.g., Col1A, NetrinG1, Lrrc15) and further subclassification of individual CAF subsets, along with more precise definition as to their origins (60–62). Finally, CAF-derived cytokines and chemokines are emerging as potential targets that can be leveraged to tune cross-talk with immune cells and augment response to immune therapy approaches. Several examples of this strategy are evident from the literature and include targeting IL-1, IL-6, CXCL12, placental growth factor, or TGF- β (24,63–66). Taken together, modulation of CAF, their soluble fac tors, and the key pathways governing their biologic properties hold promise for invigorating im mune responses against GI malignancies. Future Areas of Emphasis for Advancing Our Understanding of GI Tumor Immunology There remains a pressing need to understand fundamental features that suppress antitumor im mune responses in patients with GI malignancy. In concept, this would enable the field to priori tize novel, data-driven concepts that are common across different tumor types. Alternatively, this

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