Abstract A014: Dec2 drives tumor progression by facilitating immune evasion in pancreatic cancer

Abstract The mechanisms that regulate tumor progression and dormancy in pancreatic adenocarcinoma (PDAC) remain poorly understood. We established a murine model of early-stage PDAC that recapitulates the overall survival and metastatic recurrence patterns of patients. We isolated disseminated tumor cells (DTCs) from the livers of latent recurrent mice and found them with characteristics of dormant cells. Transcriptomic analysis indicated that not only were these cells quiescent (Ki67lo) relative to primary tumor cells, but they also exhibited high levels of the transcriptional repressor Dec2. We validated this finding in human PDAC on liver tissues from patients with stage IV disease demonstrating that isolated small clusters of DTCs were more likely Dec2hi/Ki67lo, than tumor cells in established metastases. Compared to normal pancreas, Dec2 levels are increased in PDAC tumor, and we could detect Dec2 in proliferating PDAC cells (though not at the levels as seen in dormant DTC), suggesting that Dec2 plays a role in PDAC biology beyond dormancy. We generated Dec2 knock out (KO) in murine PDAC cells for orthotopic and liver metastasis models. Loss of Dec2 markedly inhibited tumor progression and metastasis that was dependent on adaptive immune system, as the effect was abrogated when either nude hosts were used, or immunocompetent hosts were subjected to anti-CD4 and CD8 depletion. We further found that Dec2 KO cells had increased surface MHC-I as well as total MHC-I. CUT&RUN indicates that Dec2 transcriptional represses multiples genes involved in antigen presentation including H2-k1, H2-d1, B2M, Tap1 and PSMB 8,9 and 10. We found that proteosome activity was significantly increased in Dec2 KO cells and the inhibition of proteasome activity with MG132 prevented surface MHC-I display in Dec2 KO cells. We also examined the PDAC microenvironment for alterations in immune cell populations using flow cytometry and cytokines using Luminex array. Compared to WT, Dec2 KO tumors had significantly more infiltrating CD8 T cells but fewer monocytes and macrophages, particularly immunosuppressive Arg1+ macrophages. Examination of intratumoral cytokine levels showed that, relative to WT tumors, Dec2 KO had a significant decrease of Cxcl1, Ccl2 and Csf2 that are known to drive PDAC immunosuppression and a significant increase in IFN-γ. These data indicate that the anti-tumor immune mechanism induced by Dec2 KO involves not only regulation of MHC-I but also repolarization of the TME from suppressive to reactive. Taken together, we found that Dec2 plays a unique role in regulating PDAC tumor progression and dormancy. At constitutive levels Dec2 promotes pancreatic cancer progression through creating an immunosuppressive TME and immune evasion, whereas very high level of Dec2 promotes cellular dormancy. Our data identify Dec2 as a novel driver of PDAC tumor progression and dormancy and suggest that targeting Dec2 would have therapeutic potential. Citation Format: Lan Wang, Chris Harris, Orjola Prela, Wade C. Narrow, Brian Habb, Darren Carpizo. Dec2 drives tumor progression by facilitating immune evasion in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A014.