Journal
CANCER CELL
Volume 39, Issue 1, Pages 96-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.11.006
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Funding
- Cancer Prevention & Research Institute of Texas (CPRIT), United States [RR150072, RP180725, RR160101, RP190208, RP170079]
- Swim Across America Foundation Postdoctoral Fellowship
- Stand Up to Cancer Colorectal Cancer Dream Team Translational Research grant [SU2C-AACR-DT22-17]
- NIH [5P30CA142543, 1R01CA245318-01A1]
- Reece A. Overcash Jr. Distinguished Chair for Research on Colon Cancer
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This study demonstrates the importance of DNA sensing within tumor cells in triggering anti-tumor immunity in dMLH1 tumors, providing new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-beta in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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