Infiltration by interleukin-22 producing T cells promotes neutrophil recruitment and predicts favorable clinical outcome in human colorectal cancer.

Immune cell infiltration in colorectal cancer (CRC) effectively predicts clinical outcome. Interleukin -22 (IL-22), produced by immune cells, plays an important role in inflammatory bowel disease but its relevance in CRC remains unclear. Here we addressed the prognostic significance of IL-22+ cell infiltration in CRC and its effects on the composition of tumor microenvironment. Tissue microarrays (TMA) were stained with an IL-22-specific monoclonal antibody and positive immune cells were counted by expert pathologists. Results were correlated with clinical-pathological data and overall survival. Phenotypes of IL-22-producing cells were assessed by flow cytometry on cell suspensions from digested specimens. Chemokine production was evaluated in vitro upon CRC cell exposure to IL-22 and culture supernatants were used to assess neutrophil migration in vitro. Evaluation of a testing (n=425) and a validation TMA (n=89) revealed that high numbers of IL-22 tumor infiltrating immune cells were associated with improved overall survival in CRC. Ex vivo analysis indicated that IL-22 was produced by CD4+ and CD8+ polyfunctional T-cells, which also produced IL-17 and IFN-γ. Exposure of CRC cells to IL-22 promoted the release of the neutrophil recruiting chemokines CXCL1, CXCL2 and CXCL3 and enhanced neutrophil migration in vitro. Combined survival analysis revealed that the favorable prognostic significance of IL-22 in CRC relied on the presence of neutrophils and was enhanced by T cell infiltration. Altogether, CRC infiltrating IL-22-producing T cells promoted a favorable clinical outcome by recruiting beneficial neutrophils capable of enhancing T cell responses.