Lan Wang, Chris R Harris, Crissy Dudgeon, Orjola Prela, Juliana Cazarin, Ching-Hua Shih, Christina Davidson, Anthony Casabianca, Subhajyoti De, Wade C. Narrow, Jennifer Becker, Paul M. Grandgenett, Michael A. Hollingsworth, Jean L. Grem, Minsoo Kim, Yeonsun Hong, Scott Gerber, Paula M. Vertino, Chongfeng Gao, Zachary Klamer, Anna Repesh, Yansheng Hao, Allison T Ryan, Mitchell Breitenbach, Anna Bianchi, Jashodeep Datta, Brian J. Altman, Brian Haab, Darren R. Carpizo
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.