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

Harris, C. R.; Wang, L.; Dudgeon, C.; Prela, O.; Cazarin de Menezes, J.; Shih, C.-H.; Davidson, C.; Casabianca, A.; De, S.; Narrow, W.; Becker, J.; Balachandran, V.; Grandgenett, P.; Grem, J.; Hollingsworth, M. A.; Kim, M.; Hong, Y.; Gerber, S. A.; Vertino, P. M.; Gao, C.; Repesh, A.; Klamer, Z.; Hao, Y.; Altman, B. J.; Haab, B. B.; Carpizo, D. R.

doi:10.1101/2024.11.12.623005

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bioRxiv · 10.1101/2024.11.12.623005

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

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Abstract

The mechanisms that regulate cancer dormancy remain poorly understood. Using a mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified Dec2 as a gene that was upregulated in metastatic dormant tumor cells. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism as the survival benefit was abrogated in immunodeficient conditions. Dec2 promoted immune evasion by repressing multiple components of the MHC-I dependent antigen presentation pathway in tumor cells. Dec2 is a regulator of circadian rhythms, and 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, which is exploited by Dec2-overexpressing pancreatic tumors to evade the immune system.

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Harris, C. R., Wang, L., Dudgeon, C., Prela, O., Cazarin de Menezes, J., Shih, C.-H., Davidson, C., Casabianca, A., De, S., Narrow, W., Becker, J., Balachandran, V., Grandgenett, P., Grem, J., Hollingsworth, M. A., Kim, M., Hong, Y., Gerber, S. A., Vertino, P. M., Gao, C., Repesh, A., Klamer, Z., Hao, Y., Altman, B. J., Haab, B. B., Carpizo, D. R.. 2024-11-15. The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion. https://doi.org/10.1101/2024.11.12.623005

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