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

• IL-17RA signals within transformed enterocytes to promote CRC development
• IL-17RA activates ERK, p38 MAPK, and NF-κB in transformed enterocytes
• IL-17RA signals are required for growth and progression of aberrant crypt foci
• IL-17A neutralization enhances therapeutic responsiveness

SummaryInterleukin-17A (IL-17A) is a pro-inflammatory 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, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. 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 that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the 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.

Graphical AbstractFigure optionsDownload high-quality image (493 K)Download as PowerPoint slide