Understanding and tackling T cell dysfunctions towards improving colorectal cancer therapies.

Although recent advances in checkpoint-based immunotherapies have revolutionized treatments for many cancers, it has failed in microsatellite stable (MSS) colon cancer (CRC), which accounts for 90% of all colorectal tumors. Single cell RNA sequencing data by the Tejpar group led to identification of defects both in CD4 and CD8 T cells in MSS CRC which may indicate that ineffective priming and activation of T cells by dendritic cells underlies the lack of cytotoxic CD8 T cells and response to immunotherapy. The Tejpar group showed heterogeneity across tumor subsets where most MSS lack Th1 and CD8 T effector cells, but for instance CMS2 and CMS4 are enriched in Th17 and Treg, respectively, pointing to imbalances in CD4 and CD8 T cells at different levels per subtype. This heterogeneity should not be ignored when attempting to drive T cell balances to favorable Th1 and cytotoxic CD8 responses. In addition, successful activation of cytotoxic T cells can also be hampered by the basal tolerogenic interactions in the colon during homeostasis, implying the importance of studying the disease orthotopically. Therefore, I aim to characterize and manipulate CD4 and CD8 T cell (dys)functions in orthotopic patient-matched CRC models, which can suggest novel therapeutic interventions. Moreover, will provide clinically relevant colorectal tumor models with a robust interrogation toolset for phenotyping and tracking of tumor-specific immune responses.