Abstract C033: The circadian rhythm gene Dec2 promotes pancreatic cancer dormancy by facilitating immune evasion

Abstract

Abstract Metastatic recurrence following curative-intent pancreatic cancer surgery is a major clinical problem as nearly all die of this at both early and latent periods following surgery. Latent recurrences are due to reactivation of dormant tumor cells that disseminate before the primary tumor has been removed. The mechanisms that drive cancer dormancy are poorly understood in part because of the lack of animal models that recapitulate the biology of the resected patient. Here we introduce a novel mouse model of pancreatic cancer dormancy in which we establish distal pancreatic tumors by orthotopic injection, resect them four weeks later and then follow the mice for recurrence. We observed recurrence patterns and survival outcomes that mimic human patients undergoing surgery for pancreatic cancer where two thirds of the mice succumb to early metastatic recurrence (median survival 26 days) and one third of the mice (called dormant mice) live substantially long (median survival 554 days) without clinical evidence of disease yet harbor disseminated tumor cells in most organs of the body. Disseminated tumor cells isolated from the livers of dormant mice were quiescent, exhibited stem cell properties and upregulated the expression of Dec2, a transcriptional repressor previously best known for its importance in maintaining circadian rhythms. Dec2 enabled the dormant tumor cells to evade the immune system by reducing the amount of MHC1 on their surfaces, and thereby lowered the number of CD8+ T cells within the tumor microenvironment. Knocking out Dec2 significantly improved the overall survival of immunocompetent mice and increased CD8+ T cell tumor infiltration. The decrease in cell surface MHCI was likely due to impaired surface localization of the protein. RNA-seq analysis demonstrated a loss of antigen presentation pathway genes in Dec2 WT cells, particularly in genes encoding subunits of the proteasome. Proper localization of MHC1 is known to depend upon proteasome-generated peptides. By cut-and-run analysis, Dec2 bound directly to the promoters of a number of proteasomal genes, lowered expression of these genes, and decreased proteasomal activity. These studies describe a new mechanism for Dec2 in regulating cancer dormancy through its downregulation of proteasomal activity which in turn converts a hot to a cold TME by decreasing cell surface MHC1. Citation Format: Lan Wang, Orjola Prela, Ching-Hua Shih, Juliana Cazarin de Menezes, Brian Altman, Paula Vertino, Chris Harris, Darren Carpizo. The circadian rhythm gene Dec2 promotes pancreatic cancer dormancy by facilitating immune evasion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C033.