The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion

Abstract

The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro . We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.