Elucidating the molecular and cellular mechanisms of immune evasion in pancreatic cancer

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PROJECT SUMMARY/ABSTRACT Pancreatic adenocarcinoma (PDAC) carries a dismal prognosis and remains a critical unmet public health need. The recent recognition that a subset of pancreas cancer harbors potential neoantigens has intensified interest in defining the molecular and cellular mechanisms of immune evasion in PDAC to guide effective therapeutic strategies that leverage the adaptive immune system in this disease. However, difficulty in precisely defining the tumor-reactive T cell compartment has hampered prior efforts to delineate the full spectrum of mechanisms by which PDAC evades immune eradication. I hypothesize that a subset of PDAC escapes immune surveillance through dysfunction and/or altered localization of tumor-reactive T cells. Our preliminary studies, using neoantigen-expressing preclinical models of PDAC to evaluate tumor-specific immune responses, have revealed that a significant subset of tumors acquire the ability to evade immune clearance and that neoantigen-specific cos• tumor-infiltrating lymphocytes (TILs) adopt multiple states of dysfunction. Additionally, we recently demonstrated that the CD155/TIGIT axis both promotes and maintains immune evasion in PDAC (Freed-Pastor et al. Cancer Cell, in press). In this proposal, I leverage recently developed preclinical models, advances in single-cell profiling, and highly multiplexed imaging modalities to interrogate the cytotoxic T cell compartment in murine and human PDAC. Specifically, I will evaluate the effects of TIGIT/PD-1 co-blockade plus CD40 agonism on the tumor-immune microenvironment in PDAC using single-cell transcriptomic and highly multiplexed immunofluorescence technologies. I will also utilize flow cytometry and multiplexed imaging to investigate the spatiotemporal dynamics of T cell phenotypes and localization during tumor progression in preclinical models, and compare T cell responses to different neoantigens. Furthermore, I will perform high-resolution profiling on TILs isolated directly from pancreas cancer patients. Collectively, these studies hold tremendous promise for accelerating effective immune-based therapies for PDAC. The proposed research will be performed at the Koch Institute for Integrative Cancer Research at MIT, under the guidance of Dr. Tyler Jacks, an international leader in cancer biology and tumor immunology, with co-mentorship by Dr. Brian Wolpin, a leading pancreas cancer researcher at the Dana-Farber Cancer Institute. Importantly, this research strategy is one part of a comprehensive training program to support my transition to an independent research career in basic and translational cancer biology and tumor immunology. My scientific advisors (Drs. Arlene Sharpe, Stefani Spranger, and Osama Rahma) are distinguished experts with experience highly relevant to the proposed research. My long-term goal is to lead an independent academic research group, focused on deciphering the molecular and cellular mechanisms by which PDAC evades immune clearance, such that these insights can be used to guide therapeutic strategies to combat pancreas cancer and other cancers. The K08 award will provide pivotal protected time for continued mentored research and enable a successful transition to independence.