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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)96-108.e6
JournalCancer Cell
Volume39
Issue number1
DOIs
StatePublished - Jan 11 2021

Keywords

  • DNA sensing
  • MLH1
  • MSI
  • STING
  • T cell infiltration
  • cGAS
  • cancer
  • checkpoint blockade
  • cytosolic DNA
  • mismatch repair

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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