Abstract 4061: The inflammasome of tumor cells modulates the biology of tumor-infiltrating T lymphocytes in colorectal cancer

In colorectal cancer (CRC), little is known about mechanisms by which tumor cells can influence the biology of Tumor Infiltrating T lymphocytes (TILs) present in the tumor microenvironment. One of these mechanisms could be modulation of the inflammasome of tumor cells. The inflammasome is a molecular platform present in normal intestinal epithelial cells, whose effector protein, caspase-1, can rapidly mature IL-18 and generate a mucosal Th1 (IFNγ) response. However, the inflammasome status of tumor cells in CRC and its potential role in the biology of TILs are unknown yet. This prospective study aimed to determine in CRC patients (n = 50) : i) the status of the inflammasome (caspase-1 / IL-18 axis) in tumor cells according to their microsatellite status [unstable (MSI) or stable (MSS)], in relation with the density of Th1/Tc1 TILs (T-bet+) and with the levels of the prototype Th1 cytokine IFNγ, secreted in an ex vivo explant culture model of CRC we developed and ii) the impact of the inflammasome-dependent cytokines potentially secreted by tumor cells on the biology of isolated TILs. Our study delineates two major groups of patients. The first group (33% of cases, mostly MSS with a low immunoscore) featured no active caspase-1 in tumor cells, no or low levels of mature IL-18 and IFNγ and only few T-bet+ TILs in the tumor microenvironment. This profile could correspond to an immune escape mechanism facilitating tumor progression. The second group (66% of cases, both MSI and MSS with high immunoscore) featured active caspase-1 in tumor cells associated with mature IL-18 secretion, high density of T-bet+ TILs expressing IL-18Rα and IFNγ release in most cases. In addition, isolated IL-18Rα+ TILs cultured with recombinant IL-18 were able to secrete IFNγ, either left unstimulated or stimulated with anti-CD3. In these CRC, the inflammasome of tumor cells, maintained and active, can contribute to a Th1/Tc1 antitumor response elicited by TILs present in the microenvironment that can modulate tumor growth. Interestingly, in a few cases of this second group (MSI CRC), the numerous T-bet+ TILs were unable to generate a Th1 response. Noticeably, these TILs express numerous immune checkpoints including PD1 and TIGIT, potentially responsible for their exhaustion. This study is the first to delineate functional interactions between tumor cells and TILs in CRC, using ex vivo explant cultures. Altogether, our findings support the inflammasome of tumor cells as a potential n