Abstract
Abstract Many tumor types, including pancreatic adenocarcinomas, have dysregulated circadian rhythms. Previous work in our lab has shown that disseminated dormant tumor cells have increased expression of Dec2, a circadian rhythm gene, and knocking out Dec2 leads to increased overall survival in our murine resectable PDAC model. To see whether the effect of Dec2 is due to a circadian effect, we deleted the master regulator circadian gene, BMAL1. Using CRISPR-generated knockout (KO) cell lines, we saw that loss of Bmal1 completely abrogated metastasis in immunocompetent mice, but not in immunocompromised mice indicating an immune mediated mechanism. Similarly in our murine resectable PDAC model, loss of BMAL1 led to an increase in overall survival in immunocompetent mice only. Looking at the tumor microenvironment, we saw an increase in CD4+ and CD8+ T cell infiltration in the tumors derived from the BMAL KO cells. We then evaluated the BMAL KO cells for their cytokine secretion and saw that loss of BMAL1 led to decreased interleukin-1 receptor antagonist both in vitro and in vivo. IL-Ra has been shown in literature to suppress the immunogenic anti-tumor response by impairing the activities of APCs, CD4+ and CD8+ T cells and disruption of IL-1Ra can reverse the TME towards more immunogenic leading to an antitumor effect. Taken together these studies implicate Bmal1 in regulating anti-tumor immunity in PDAC through its regulation of IL-1Ra secretion. This is a novel function for a circadian rhythm gene in PDAC biology. Citation Format: Orjola Prela, Lan Wang, Chris Harris, Darren Carpizo. The circadian master regulator BMAL1 blocks immune cell recognition of pancreatic ductal adenocarcinomas via tumor-derived interleukin-1 receptor antagonist [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B057.
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