The interleukin 22 pathway interacts with mutant KRAS to promote poor prognosis in colon cancer.
McCuaig S., Barras D., Mann E., Friedrich M., Bullers SJ., Janney A., Garner LC., Domingo E., Koelzer VH., Delorenzi M., Tejpar S., Maughan TS., West NR., Powrie F.
PURPOSE:The cytokine interleukin 22 (IL-22) promotes tumor progression in murine models of colorectal cancer (CRC). However, the clinical significance of IL-22 in human CRC remains unclear. We sought to determine whether the IL-22 pathway is associated with prognosis in human CRC, and to identify mechanisms by which IL-22 can influence disease progression. EXPERIMENTAL DESIGN:Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N=566) and verification (PETACC3 clinical trial, N=752) datasets were used to investigate the association between IL-22 receptor expression (encoded by the genes IL22RA1and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL-22 and mutant KRAS were elucidated using human CRC cell lines and primary tumor organoids. RESULTS:Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL-22 receptor, and KRASmutation (RFS: HR=2.93, P=0.0006; OS: HR=2.45, P=0.0023). KRASmutations showed a similar interaction with IL10RB, and conferred the worst prognosis in tumors with high expression of both IL22RA1and IL10RB(RFS: HR=3.81, P=0.0036; OS: HR=3.90, P=0.0050). Analysis of human CRC cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRASmutation status, showed that IL-22 and mutant KRAScooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway. CONCLUSIONS:Interactions between KRASand IL-22 signaling may underlie a previously unrecognized subset of clinically aggressive CRC that could benefit from therapeutic modulation of the IL-22 pathway.