Handbook of Targeted Cancer Therapy and Immunotherapy

109 immune response. Some cytokines of notable importance in the setting of GI tumors that are supported by data from the literature include transforming growth factor- β (TGF- β ), interleukin-6 (IL-6), IL-8, and vascular endothelial growth factor (VEGF), among others (15–18). In general, cytokine profiles are skewed away from the Th1 type, which can promote optimal immune responses from cytotoxic T and natural killer (NK) cells. Instead, Th2 and Th17 signatures are far more common in these patients, which enable maintenance of functionally suppressive immune cells including T regulatory cells (T regs), myeloid-derived suppressor cells (MDSC) or M2-polarized, tumor-associated macrophages (TAMs) (19–21). Other evidence supports a role for cytokines in the colony-stimulating factor family, such as granulocyte macrophage-colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), and macrophage-colony-stimulating factor (M-CSF), which enable preferential expansion of myeloid cells (22,23). Parallel to these immune changes, tumors confer other bi ologic advantages from cytokines and growth factors that enable angiogenesis including basic fibroblast growth factor (bFGF), IL-8, and VEGF. Using VEGF as an example, many of these fac tors can simultaneously influence multiple facets of the TME by concurrently enabling blood vessel formation and acting via its receptor that is expressed on immune cells to further promote expansion of T regs and MDSC. This cytokine profile can also be coupled with dysregulation of chemokine gradients in a manner that preferentially attracts suppressive immune cells. For ex ample, GI tumors and their stroma can produce CXCL12/SDF-1 that limits access of T cells into the TME (24). Data also continue to emerge linking distinct oncogenic driver mutations in tumor cells with production of specific chemokine mediators. One prominent example of this was from Li et al., who demonstrated oncogenic KRAS can enable myeloid infiltration in a manner that was dependent upon CXCL1 production by the tumor cells (25). Other connections between Wnt/ β -catenin signal ing or LKB1 mutations and reduced T-cell infiltration have also been noted (26,27). These observa tions support the idea that individualized immune signatures in the TME are subject to influence by the genomic features of the tumor itself.

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