Interleukin 22 protects colorectal cancer cells from chemotherapy by activating the STAT3 pathway and inducing autocrine expression of interleukin 8

• Identify IL-22 as a novel chemoresistance-related cytokine in colorectal cancer
• IL-22 levels in tumors and serum are associated with resistance to FOLFOX treatment.
• IL-22 promotes resistance to 5-FU and OXA by activating the STAT3 pathway.
• IL-22 promotes chemoresistance by inducing IL-8 autocrine through STAT3 activation.

Resistance to chemotherapy is the major cause of colorectal cancer (CRC) treatment failure. The cytokine IL-22, which is produced by T cells and NK cells, is associated with tumorigenesis and tumor progression in cancers. However, the role of IL-22 in chemoresistance has not been investigated. We found that IL-22 levels in tumor tissues and peripheral blood were associated with chemoresistance and indicate poor prognosis for patients who received FOLFOX chemotherapy. In CRC cells, IL-22 was able to attenuate the cytotoxic and apoptosis-inducing effects of 5-FU and OXA by activating the STAT3 pathway and subsequently increasing the expression of anti-apoptotic genes. In addition, IL-22 conferred resistance to 5-FU and OXA by inducing IL-8 autocrine expression through STAT3 activation. Our findings identify IL-22 as a novel chemoresistance cytokine and may be a useful prognostic biomarker for CRC patients receiving FOLFOX chemotherapy.