Prognostic Role of Inflammasome Components in Human Colorectal Cancer.

Simple Summary Inflammasomes are critically involved in gut epithelial homeostasis, immunosurveillance and in controlling tumorigenesis mechanisms. Data on the role of inflammasomes in tumorigenesis are mostly provided by transcriptomic analyses of bulk tumors, eluding a potential specific role of intrinsic epithelial inflammasomes. Therefore, we investigated the expression of inflammasome components in intestinal epithelial cells, at the protein level in patient tissues and assessed the correlation with clinicopathological parameters. We found that downregulation of the epithelial expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) and IL-18 was associated with more advanced disease and worse patients' outcome. Furthermore, the loss of both epithelial and stromal IL-18 was also associated with worse disease outcome. Finally, we identified an epithelial innate immune protein profile combining NLRP6 and IL-18 that stratified patients for better clinical prognosis. Together, analysis of epithelial inflammasomes may help clinical decisions for better prognostic assessment and may identify new therapeutic targets in colorectal cancer. (1) We wanted to assess the prognostic impact of inflammasomes involved in gut epithelial homeostasis and the development of human colorectal cancer (CRC). (2) We investigated the expression of inflammasome components in colonic epithelial cells at the protein level in patient tissues, through an immunofluorescence assay. (3) In a cohort of 104 patients, we found that all inflammasome components were downregulated in CRC. Loss of epithelial (but not stromal) expression of NLRP6, caspase-1 and IL-18 was associated with an increased mortality of 72%, 58% and 68% respectively and to disease progression into metastasis. The loss of epithelial and stromal IL-18 but not NLRP6, was associated to lower tumor immune infiltrates in the lymphoid compartment and higher Programmed cell Death receptor 1 (PD-1) expression. Finally, we found that combined downregulation of IL-18 and NLRP6 was associated with a worse outcome. Indeed, 5-year survival rates were 26% for the NLRP6low/IL-18low tumors, compared to 64.4% for the entire cohort. This downregulation was associated with a more advanced disease (p < 0.0001) and a trend to lower lymphoid cell infiltration. (4) We identified critical inflammasome markers that may help in better stratifying patients for prognosis in CRC and could help clinicians to determine which patients may benefit from immunotherapies.