Targeting IL-17 for cancer-associated inflammation and immunity

Abstract

Abstract Interleukin-17A (IL-17A) is a proinflammatory cytokine whose expression has been linked to rapid malignant progression of colorectal cancer (CRC) and resistance to therapy. Ablation of IL-17A or its type A receptor (IL-17RA) in mouse models of colonic tumorigenesis confirmed their tumor-promoting function. 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. Consistent with the notion that IL-17 promotes tumor-associated inflammation and inhibits anti-tumor immunity, ablation of IL-17RA resulted in reduced infiltration of CD11b+ cells and elevated numbers and activity of cytotoxic T lymphocytes in colorectal tumors. Using anti-IL-17 as an adjuvant therapy may improve the efficacy and safety of current cancer immunotherapeutic schemes.