The Role of Mutant p53 in Regulating T-cell Immune Evasion in Pancreatic Adenocarcinoma and Other Cancers

项目总结/文摘

Project Summary/Abstract Harnessing a patient’s immune system by attenuating endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection for multiple tumor types. Nonetheless, pancreatic ductal adenocarcinoma (PDAC) remains largely resistant to all therapies, including immunotherapies, leading to its notoriety as one of the most lethal malignancies, with a 6% 5-year survival rate. To design efficacious treatments for PDAC, it is important to understand the mechanism by which PDAC escapes the host immune system. Unlike immunotherapy-responsive tumor types such as melanoma, PDAC is mutationally homogeneous, with up to 75% of tumors possessing mutations in the tumor suppressor p53. p53 loss is well-described to mediate tumor escape from apoptosis and senescence. p53 missense mutants (mtp53) also acquire gain-of-function activities distinct from p53’s wild-type activity. Pre-clinical studies support that mtp53 mediate tumor escape from immune surveillance by modulating innate immune effectors, including NK cells and macrophages. Few studies have been completed, however, investigating the role of mtp53 in altering adaptive immune effectors, including cytotoxic T-cells. Understanding the role of mtp53 in mediating T-cell infiltration and function in PDAC would provide a novel framework to understand and overcome resistance to cancer immunotherapy. In this project, I will determine whether various structure-function classes of mtp53 impact PDAC oncogenesis or tumor maintenance by impacting T-cell function. I hypothesize that p53 mutations mediate evasion of T-cell- mediated killing and immunotherapy in PDAC and other tumors, and that mtp53 class is an important factor in this process. To test this hypothesis, I will establish whether p53 tumor mutational status influences T-cell infiltration, phenotype, and functionality in PDAC, using novel PDAC murine models and flow cytometry, CyTOF, Caspase, and cytokine secretion assays, and determine whether p53 mutational status impacts response to immune checkpoint inhibitors. With the successful completion of these aims, I will ascertain if p53 mutational status promotes T-cell-mediated immune escape in PDAC. These results would elucidate the role of mtp53 activating mutations in tumorigenesis, identify potentially-targetable downstream effectors unique to mtp53, and provide rationale to investigate mtp53 immune-regulation in PDAC and other tumor types.