? Project 3 (The Functional Contribution of Tumor Immunity to PDAC) PDAC is marked by an extensive desmoplastic reaction/stroma consisting of myofibroblasts, extracellular matrix (ECM) and immune cells, and oncogenic Kras is a critical driver of PDAC genesis and maintenance. The functional importance of PDAC microenvironment and its various cellular constituent in oncogenic Kras dependent and independent PDAC maintenance remains an area of active investigation, but there is minimal knowledge addressing the role of oncogenic Kras in shaping tumor immunity, in particular the T cell response. The central mission of our P01 program is to collectively identify a range of novel Kras driven vulnerable nodes that can be inhibited as a treatment for this devastating disease. The inducible oncogenic Kras genetically engineered mouse model (GEMM) of PDAC indicated that tumor regression could be achieved via oncogenic Kras extinction, a process accompanied by depletion of oncogenic Kras dependent cancer cells and significant, albeit incompletely characterized, alterations in immune response. Studies from Projects 1 and 2 using this PDAC GEMM also offered mechanistic insights into spontaneous tumor relapse, which includes the presence oncogenic Kras extinction resistant cells (KRC) with distinct metabolic dependencies (OXPHOS), and the emergence of tumors with activation of YAP or other yet unidentified mechanism for PDAC maintenance. Projects 1 and 2 will focus on exploiting the metabolic vulnerabilities of cancer cells and the central hypothesis of Project 3 is that ?oncogenic Kras and its signaling surrogates have a causal effect on tumor immunity to facilitate cancer progression?. Knowledge of this oncogenic Kras driven circuitry may illuminate therapeutic points of intervention in the tumor microenvironment and offer an improved understanding of how to deploy checkpoint blockade therapies in combination with cancer cell-specific therapies targeting metabolic or salvage pathways. The study could inform combination treatment that includes checkpoint blockade therapies ? i.e., whether OXPHOS inhibition or autophagy inhibition can help or impede such immunotherapy strategies. The studies proposed by Project 3 are highly interconnected with studies proposed in Projects 1 and 2, and rely directly on all the Cores of this P01. Specifically, the integrated specific aims of Project 3 are to investigate Kras* dependent and independent immune response in PDAC (Aim 1), to determine the impact of targeting metabolic and salvage pathways on tumor immunity (Aim 2) and to identify novel strategies to enhance efficacy of checkpoint blockade immunotherapy in PDAC (Aim 3). This effort is integral to the overall P01 Program Goal of developing a mechanism-based rational combination strategy that can lead to meaningful therapeutic advances for PDAC patients.
? Project 3 (The Functional Contribution of Tumor Immunity in PDAC) Oncogenic Ras is a key driver of PDAC pathogenesis and Project 3 will investigate the functional role of oncogenic Kras (Kras*) and its downstream effectors in the recruitment of immune cells that contribute to suppression of immune surveillance. Additionally, this project will identify the specific role of immune response in Kras* dependent PDAC, Kras* extinction associated regression and Kras* independent relapse. The impact of targeting such putative cancer cell autonomous pathways on tumor immunity will be explored with the goal of identifying an optimal opportunity to combine immune checkpoint blockade (immunotherapy) with Kras* dependent targets in clinic.
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