Abstract 4048: The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion

Abstract The mechanisms that regulate cancer dormancy remain poorly understood. Using an orthotopic mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified the transcriptional repressor factor Dec2 (Bhlhe41) as a gene that was upregulated in metastatic dormant tumor cells from the liver. To understand how Dec2 regulates dormancy, we deleted it from the murine pancreatic cancer cells and implanted them in the model. Following resection, mice implanted with Dec2 KO cells demonstrated a striking improvement in survival compared to the mice with Dec2 WT cells. This difference in survival was abrogated when nude mice were used as hosts indicating the survival difference is from an immune mediated mechanism. Pancreatic cancer is a highly immunosuppressive tumor due to both a relatively low expression of major histocompatibility complex class I (MHC-I)-dependent antigen presentation and an abundance of myeloid-derived suppressor cells that lead to poor T cell trafficking and activation. We found that deletion of Dec2 overcame both of these mechanisms to restore anti-tumor immunity that inhibited tumor growth not only in primary tumors as well as metastases. Dec2 suppresses MHC-I antigen presentation by repressing multiple genes in the antigen presentation pathway including H2-k1, H2-d1, Tap1, and B2m as well as the source of tumor antigens from the proteosome by repressing multiple proteasome genes. Loss of Dec2 repolarized the tumor immune microenvironment by decreasing expression of multiple immunosuppressive cytokines such as Cxcl1, Ccl2 and Csf2 in tumors. We conclude that Dec2 facilitates both pancreatic tumor growth and dormancy by regulating tumor cell MHCI antigen presentation. Dec2 is known to function as part of a negative accessory arm of the molecular circadian clock. We found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock. Citation Format: Lan Wang, Chris Harris, Orjola Prela, Wade Narrow, Jennifer L. Becker, Juliana Cazarin de Menezes, Darren R. Carpizo. The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4048.