COMBINED TUMOR AND STROMAL TARGETING TO IMPROVE PANCREATIC CANCER RESPONSE TO IMMUNOTHERAPY

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 DESCRIPTION (provided by applicant): The prognosis for pancreatic cancer (PaC) patients is dismal. The application of immunotherapy holds the promise to revolutionize PaC patient outcomes. Unfortunately, attempts at immunotherapy in PaC, to date, have not achieved significant clinical benefits as single agents. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most pancreatic ductal adenocarcinomas (PDAC). Two major drivers of this tumor protective microenvironment include a dense fibrotic tumor stroma and robust infiltration by tumor-supportive myeloid cells. High stromal density provides a barrier to T cell infiltration and function. These data suggest that we could improve PaC patient outcomes, if we could identify therapeutics that reprogram the protective TME to facilitate immunotherapy. One such approach is to target the oncogenic pathways that induce the fibrotic and suppressive PDAC TME. Recently, we have identified focal adhesion kinase (FAK)-1, which is hyperactivated in the presence of mutated Kras, as a major driver of the fibrotic and inflammatory (fibro-inflammatory) TME of PDAC tumors. We have discovered that in human PDAC, elevated FAK activity correlates with higher fibrosis levels, excessive myeloid cell infiltration, and poor T cell responses. These data suggest that FAK is a key mediator of the fibro-inflammatory microenvironment that blocks immunotherapeutic efficacy. We have found that FAK inhibition dramatically reduced fibrosis and inflammatory myeloid cell infiltration, and improved T cell function in PaC mouse models. Our hypothesis is that: Reciprocal crosstalk between Kras-mutant pancreatic tumors and stromal cells regulates inflammatory fibrosis and prevents responsiveness to immunotherapy. To test this hypothesis, we will: 1) Determine the mechanisms by which Kras-driven FAK activity regulates fibrosis and local immunosuppression. 2) Determine the impact of stromal FAK signaling on fibrosis and tumor progression. 3) Determine the mechanisms by which FAK blockade improves immunotherapy. Significance: Our preliminary data strongly support the use of FAK inhibitors in combination with chemotherapy and/or checkpoint antagonists in PDAC patients. However, understanding the mechanisms by which FAK signaling in PDAC tumor and stromal cells drive tumor fibrosis and immunosuppression is critical to designing effective clinica trials. Additionally, these studies will contribute to our understanding of how tumor cells and stromal cells crosstalk to generate resistance to immunotherapy. This is a significant gap in our understanding of the immunobiology of PaC, which has thwarted the effectiveness of therapy to date.