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Simple Summary  The evolution of colorectal cancer (CRC) is influenced by complex interactions between tumor cells and tumor-infiltrating lymphocytes (TILs). Optimized immunotherapies to boost the potential anti-tumor T-cell response are still needed in CRC. A good candidate is the inflammasome pathway that bridges innate and adaptive immunity via the caspase-1/interleukin-18 (IL-18) axis, able to elicit a T-helper/cytotoxic (Th1/Tc1) anti-tumor response. This study aimed to determine the status of the caspase-1/IL-18 axis in tumor cells and its potential modulatory role on TILs in CRC. Using cohorts of CRC patients and an ex vivo explant culture model allowing functional and multiparametric approaches, we demonstrate that tumor cells in the majority of CRCs can be considered as innate immune cells that display a functional caspase-1/IL-18 axis able to modulate the adaptive Th1/Tc1 anti-tumor response of TILs. Furthermore, the identification of three distinct subgroups of CRC will provide a rationale for future strategies targeting the inflammasome pathway in CRC.    Abstract  In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.

cancers

The Caspase-1/IL-18 Axis of the Inflammasome in Tumor Cells: A Modulator of the Th1/Tc1 Response of Tumor-Infiltrating T Lymphocytes in Colorectal Cancer