Abstract
Simple SummaryThe 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.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.
Highlights
The evolution of many solid tumors including colorectal cancer (CRC) is influenced by intricate and complex interactions between tumor and immune cells of the tumor microenvironment, depending on many different intrinsic factors including tissue-specific factors and genetic abnormalities of the tumor
In 90% of microsatellite instable (MSI) CRCs and 70% of Microsatellite stable (MSS) CRCs, an intense IL-18 immunostaining was observed in more than 50% of tumor cells, which was associated with a higher density of intraepithelial CD8+ and T-box expressed in T cells (Tbet)+ TIL (IEL-TIL). These findings suggest that IL-18 produced by tumor cells can influence the density of the IEL-TIL infiltrate that we and others previously reported to be higher in MSI and a subgroup of MSS CRCs
Our findings showed that the presence of an activated caspase-1/IL-18 axis in tumor cells in the majority of CRCs led to the secretion of mature IL-18
Summary
The evolution of many solid tumors including colorectal cancer (CRC) is influenced by intricate and complex interactions between tumor and immune cells of the tumor microenvironment, depending on many different intrinsic factors including tissue-specific factors and genetic abnormalities of the tumor These interactions lead to the development of a local immune response that can have immunosuppressive or immunostimulatory properties. We recently demonstrated that a preexisting in situ Th1/Tc1 immune response—identified by the expression of the transcription factor T-box expressed in T cells (Tbet)—positively impacted prognosis in MSI as well as in MSS CRC [7] This anti-tumor immune response can be counterbalanced by inhibitory signaling pathways including immune checkpoint receptors (ICPs), and their ligands such as the programmed death receptor-1 (PD-1) or cytotoxic T lymphocyteassociated protein 4 (CTLA4) pathways [7,8], that can be blocked by specific antibodies defined as immune checkpoint inhibitors (ICIs). Treatment with ICIs only leads to objective and durable responses in 30% to 50% of metastatic MSI CRC cases (mono-or combotherapy) and to a very low response rate in MSS CRC [9,10,11]
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