Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY/ABSTRACT I propose to functionally interrogate mechanisms of cancer immune evasion and immunotherapy resistance in powerful new mouse models of colorectal cancer (CRC). Immune checkpoint blockade (ICB) has revolutionized treatment of multiple solid tumor types but is nevertheless ineffective in most cancers. I hypothesize that this is due in part to distinct programs of T cell dysfunction that respond poorly to ICB, such as that programmed by suboptimal T cell priming. While microsatellite instable (MSI) CRC responds remarkably well to ICB, likely due to a high burden of mutation-derived antigens (neoantigens), most CRC (~88%) is microsatellite stable (MSS) and does not respond. However, MSS CRC is characterized by a higher burden of mutations than other solid tumor types that do respond to ICB, like kidney cancer. My own analysis of human MSS CRC sequencing revealed that all tumors expressed at least two clonal neoantigens with strong predicted binding to HLA-I, but that these neoantigens were expressed at significantly lower levels than those in MSI CRC. This suggests that neoantigen expression levels, in addition to burden, may play an important role in the antitumor T cell response. To test this, I developed a colonoscopy-guided orthotopic transplant model of CRC employing isogenic organoids with varying levels of expression of model CD8+ T cell neoantigens. High expression resulted in organoid rejection, while low expression resulted in poor T cell priming with immediate dysfunction and tumor escape. Tumor infiltrating T cells in my low neoantigen-expressing model and human MSS CRC showed signatures of tolerogenic dysfunction, distinct from canonical “exhaustion” and consistent with suboptimal priming. These analyses also identified the orphan nuclear receptor 4A subfamily genes Nr4a1, Nr4a2, and Nr4a3—an exciting new class of T cell checkpoint—as potentially central mediators of this process. Aim 1 will functionally interrogate Nr4a1-3 in T cell priming and dysfunction and investigate their potential as therapeutic targets in CRC. Aim 2 will determine whether existing therapies that boost T cell priming (CD40 agonism, vaccination) can rescue suboptimal T cell priming in CRC and delineate T cell intrinsic and extrinsic mechanisms of efficacy and resistance. The overarching goal of these aims is to deepen our mechanistic understanding of non-canonical T cell dysfunction in CRC and identify new therapeutic strategies to reverse it. This holds substantial promise for the majority of CRC and other cancers that do not respond to ICB and may guide novel combination clinical trials. This proposal is innovative in bringing together cutting-edge mouse models of cancer and advanced tools in immunology. Its completion should bring clarity to the outstanding question of why CRC, the second leading cause of cancer deaths worldwide, is generally nonresponsive to current immunotherapies. The K22 award will help me execute these aims and generate preliminary data that will form a foundation for competitive R01 applications, publications, and a successful independent research program, as well as give me the flexibility to augment my immunology training through NASDC course offerings.
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