DNA sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity Journal Article
| Authors: | Lu, C.; Guan, J.; Lu, S.; Jin, Q.; Rousseau, B.; Lu, T.; Stephens, D.; Zhang, H.; Zhu, J.; Yang, M.; Ren, Z.; Liang, Y.; Liu, Z.; Han, C.; Liu, L.; Cao, X.; Zhang, A.; Qiao, J.; Batten, K.; Chen, M.; Castrillon, D. H.; Wang, T.; Li, B.; Diaz, L. A. Jr; Li, G. M.; Fu, Y. X. |
| Article Title: | DNA sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity |
| Abstract: | 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-β 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. © 2020 Elsevier Inc. About 50% of patients with dMMR cancers are objectively responsive to immunotherapy. In addition to neoantigens, Lu et al. find that dMMR-mediated cytosolic DNA sensing by cGAS-STING pathway in tumor cells contributes to such clinical benefits, while impaired expression of cGAS-STING pathway is associated with drug resistance. © 2020 Elsevier Inc. |
| Keywords: | mismatch repair; msi; mlh1; checkpoint blockade; cytosolic dna; cancer; dna sensing; sting; cgas; t cell infiltration |
| Journal Title: | Cancer Cell |
| Volume: | 39 |
| Issue: | 1 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2021-01-11 |
| Start Page: | 96 |
| End Page: | 108.e6 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2020.11.006 |
| PUBMED: | 33338425 |
| PROVIDER: | scopus |
| PMCID: | PMC9477183 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2021 -- Source: Scopus |
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