Interleukin-17 Receptor A Signaling in Transformed Enterocytes Promotes Early Colorectal Tumorigenesis

Abstract

Summary Interleukin-17A (IL-17A) is a proinflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, how IL-17RA engagement promotes colonic tumorigenesis is unknown, as IL-17RA is expressed in many cell types in the tumor microenvironment, including hematopoietic, fibroblastoid and epithelial cells. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK and NF-κB signaling and promotes the proliferation of tumorigenic enterocytes who just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL-17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer.

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

“…In particular, the IL-23/IL-17 axis has been linked to worse outcome in CRC patients 32 and has been recognized to drive colorectal carcinogenesis in experimental models, 33 through a variety of mechanisms that include a direct promotion of enterocyte proliferation by IL-17. 34 Conversely, CD8 C T cell infiltration has been recognized as a major prognostic factor in CRC prognosis, 10 an event probably favored by follicular helper response and tertiary lymphoid structure formation, 11,35 indicating the attempts of protective immune-surveillance to counteract tumor progression.…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…129 Indeed, one such microorganism [the enterotoxigenic Bacteroides fragilis (ETBF)] induces pathogenic Th17 responses to promote Functional mechanisms of IL-17 family cytokines X Song et al intestinal tumorigenesis in Apc Min/+ mice. 130 Recently, IL-17RA signaling in transformed enterocytes were demonstrated to be essential for intestinal tumor development, 131 indicating that IL-17 directly promoted tumor cell proliferation; however, IL-17C signaling was also diminished in this system. IL-17 and IL-23 signaling also promote chemical-induced skin cancer development because a deficiency in IL-17, IL-17RA or IL-23 in mice inhibits the cutaneous carcinogenesis induced by 9,10-dimethyl-1,2-benzanthracene (DMBA) plus 12-Otetradecanoyl-phorbol acetate (TPA).…”

“…165 The dysregulated microbiota has been shown to drive IL-17 production in Th17 cells and to promote the growth of transformed enterocytes in colorectal cancer. 131 However, microbiota-driven IL-17C primarily inhibits the apoptosis of transformed enterocytes by inducing Bcl-2 and Bcl-x L expression in these cells in an autocrine manner to promote tumorigenesis. 165 Thus, IL-17C and IL-17 promote intestinal cancer development via distinct mechanisms, and the dysregulated microbiota, such as bacteria in the Enterobacteriaceae family, can mediate cancer pathogenesis by regulating both IL-17C and IL-17.…”

Enhanced gut barrier integrity sensitizes colon cancer to immune therapy

“…Consistent with this paradigm, a significant body of literature supports a major role for microbially-driven type 17 T-cell immunity (including Th17 and γδT-cell subsets) in colon cancer. 7–10 Importantly, analysis of clinical CRC samples has revealed an inverse relationship in CD8+ cytotoxic T-lymphocyte (CTL)/Th17 cell ratio between MMR-deficient (high CTL, low Th17) and ICI-resistant MMR-proficient (low CTL, high Th17) tumors; 11 supporting the notion that the outcome of immune therapy in CRC may be dependent on the ability to alter the CTL – Th17 cell balance.…”