DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity.
DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity.
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DOI：
10.1016/j.ccell.2020.11.006
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发表时间：
2021-01-11
期刊：
影响因子：
50.3
通讯作者：
Fu, Yang-Xin
中科院分区：
文献类型：
--
作者：
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., Jr.;Li, Guo-Min;Fu, Yang-Xin
DNA错配修复缺陷(DMMR)的高突变肿瘤中新抗原的增加被认为是抗PD-1治疗中高客观应答率的主要原因。然而，目前对其耐药机制尚不完全清楚。利用MMR基因MLH1缺陷的肿瘤模型，我们发现dMLH1肿瘤细胞以cGAS依赖的方式积聚胞浆DNA并产生干扰素-β，这使得dMLH1肿瘤进展缓慢，对检查点封锁高度敏感。在新抗原固定的模型中，dMLH1肿瘤有效地诱导T细胞启动，并失去对检查点治疗的抵抗力，而不依赖于肿瘤突变负担。因此，肿瘤细胞中的刺痛或cGAS的丢失减少了肿瘤对T细胞的渗透，并赋予了对检查点封锁的抵抗力。在临床上，cGAS/STIN在人类dMMR癌中的下调与预后不良相关。我们得出结论，肿瘤细胞内的DNA传感对于dMMR触发的抗肿瘤免疫是必不可少的。本研究为抗dMMR肿瘤免疫治疗提供了新的机制和生物标志物。大约50%的dMMR癌症患者对免疫治疗有客观反应。除了新的抗原，Lu等人还发现，在肿瘤细胞中，dMMR通过cGAS-STING途径介导的胞浆DNA传感有助于这种临床益处，而cGAS-STING途径的表达受损与耐药性有关。
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, down-regulation 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. 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 associates with drug resistance.
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影响因子：
29.4
作者：
Boland CR;Goel A
通讯作者：
Goel A
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
3.4
作者：
Koelzer, Viktor Hendrik;Baker, Kristi;Zlobec, Inti
通讯作者：
Zlobec, Inti
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
28.2
作者：
Llosa, Nicolas J.;Cruise, Michael;Housseau, Franck
通讯作者：
Housseau, Franck