The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer.

Purpose: The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.

Experimental Design: Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, = 566) and verification (PETACC3 clinical trial, = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes and ), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.

Results: Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of , the alpha subunit of the heterodimeric IL22 receptor, and mutation [relapse-free survival (RFS): HR = 2.93, = 0.0006; overall survival (OS): HR = 2.45, = 0.0023]. mutations showed a similar interaction with and conferred the worst prognosis in tumors with high expression of both and (RFS: HR = 3.81, = 0.0036; OS: HR = 3.90, = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.

Conclusions: Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.