Cited by 285Cancer Immunotherapy and Biomarkersinterferon and immune responsesImmunotherapy and Immune Responses

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DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity

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Lu, Changzheng, Guan, Junhong, Lu, Steve, Jin, Qihuang, Rousseau, Benoit, Lu, Tianshi, Stephens, Dennis, Zhang, Hongyi, Zhu, Jiankun, Yang, Mingming, Ren, Zhenhua, Liang, Yong, Liu, Zhida, Han, Chuanhui, Liu, Longchao, Cao, Xuezhi, Zhang, Anli, Qiao, Jian, Batten, Kimberly, Chen, Mingyi, Castrillon, Diego H., Wang, Tao, Li, Bo, Diaz, Luis A., Li, Guo-Min, Fu, Yang-Xin·2021·Cancer Cell

DOI 10.1016/j.ccell.2020.11.006PMC PMC9477183

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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.

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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., Li, G.-M., & Fu, Y.-X.
Affiliations: The University of Texas Southwestern Medical Center (US)
Howard Hughes Medical Institute (US)
Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Li, Guo-Min
Fu, Yang-Xin
ORCID: Lu, Changzheng
Guan, Junhong
Lu, Steve
Jin, Qihuang
Lu, Tianshi
Zhang, Hongyi
Zhu, Jiankun
Yang, Mingming
Ren, Zhenhua
Liang, Yong
Liu, Zhida
Han, Chuanhui
Liu, Longchao
Cao, Xuezhi
Zhang, Anli
Qiao, Jian
Chen, Mingyi
Wang, Tao
Li, Bo
Diaz, Luis A.
Li, Guo-Min
Fu, Yang-Xin
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2021-01
Volume: 39
Issue: 1
Pages: 96-108.e6
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2020.11.006
PMC: PMC9477183
OpenAlex: W3112754342
Cited by: 285
References: 60
Citations by year: 2026: 36 · 2025: 51 · 2024: 53 · 2023: 66 · 2022: 46 · 2021: 32
FWCI: 13.09
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Entertainment Industry Foundation
Amaldi Research Center
Astellas Pharma US
Johns Hopkins University
Merck
University of Texas Southwestern Medical Center (RP180725)
Novartis
Bayer Fund
Cancer Prevention and Research Institute of Texas (RR150072, RR160101)
Jounce Therapeutics
Gilead Sciences
Servier
American Association for Cancer Research
National Institutes of Health (1R01CA245318-01A1, 5P30CA142543)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: mismatch repair deficiency, MLH1, cytosolic DNA sensing, cGAS-STING pathway, interferon-beta, neoantigens, anti-PD-1 therapy, immune checkpoint blockade, tumor immunogenicity, T cell priming, tumor mutational burden, drug resistance, prognostic factors, cancer immunotherapy
MeSH terms: MutL Protein Homolog 1, Immune Checkpoint Inhibitors, STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Female, Humans, Membrane Proteins, Neoplasm Transplantation, Neoplasms, Nucleotidyltransferases, Prognosis, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Interferon-beta, Cell Line, Tumor, Mice, DNA Mismatch Repair

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DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity

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