@article{63ccec5a828d4234a966fc10d1ff25f7,
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.",
keywords = "DNA sensing, MLH1, MSI, STING, T cell infiltration, cGAS, cancer, checkpoint blockade, cytosolic DNA, mismatch repair",
author = "Changzheng Lu and Junhong Guan and Steve Lu and Qihuang Jin and Benoit Rousseau and Tianshi Lu and Dennis Stephens and Hongyi Zhang and Jiankun Zhu and Mingming Yang and Zhenhua Ren and Yong Liang and Zhida Liu and Chuanhui Han and Longchao Liu and Xuezhi Cao and Anli Zhang and Jian Qiao and Kimberly Batten and Mingyi Chen and Castrillon, {Diego H.} and Tao Wang and Bo Li and Diaz, {Luis A.} and Li, {Guo Min} and Fu, {Yang Xin}",
note = "Funding Information: We thank the UT Southwestern Flow Cytometry Facility, Institutional Animal Care and Use Committee Animal Resources Center, and Animal Research Center. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology, and G.-M.L. holds the Reece A. Overcash Jr. Distinguished Chair for Research on Colon Cancer. We thank Professor David Farrar for providing the CL4 mice, and Drs. Damiana Chiavolini and Jonathan Feinberg for language polishing on the manuscript. This work was supported in part by Cancer Prevention & Research Institute of Texas (CPRIT), United States grants RR150072 and RP180725 to Y.-X.F. RR160101 to G.-M.L, RP190208 To T.W. RP170079 to B.L. Both Y.-X.F. and G.-M.L. are CPRIT Scholars in Cancer Research. B.R. has support from The Swim Across America Foundation Postdoctoral Fellowship. Research was partially supported by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research grant (SU2C-AACR-DT22-17). Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. This work was also suported by NIH 5P30CA142543 to T.W and 1R01CA245318-01A1 to B.L. Conceptualization, C.L. J.G. G.-M.L. and Y.-X.F.; Methodology, C.L. J.G. S.L. Q.J. B.R. D.S. and L.A.D.; Investigation, C.L. J.G. S.L. Q.J. B.R. D.S. M.Y. T.L. and H.Z.; Formal Analysis, C.L. J.G. S.L. Q.J. D.S. T.L. H.Z. B.L. T.W. and K.B.; Resources, M.C. J.Z. Y.L. Z.R. A.Z. J.Q. Z.L. C.H. L.L. and X.C.; Writing – Original Draft, C.L. and Y.-X.F; Writing – Review & Editing, C.L. J.Q. D.H.C. G.-M.L. and Y.-X.F.; Supervision, G.-M.L. and Y.-X.F.; Funding Acquisition, G.-M.L. and Y.-X.F. B.R. has served in a consulting/advisory role for Bayer, Roche, Novartis, Gilead, and Servier, and has received travel, accommodations, and expenses from Bayer, Servier, and Astellas. L.A.D. is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. He is a paid consultant to PGDx, 4Paws (PetDx), Innovatus CP, Se'er, Kinnate, and Neophore. He is an uncompensated consultant for Merck but has received research support for clinical trials from Merck. L.A.D. is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and L.A.D. He holds equity in PGDx, Jounce Therapeutics, Thrive Earlier Detection, Se'er, Kinnate, and Neophore. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. Funding Information: We thank the UT Southwestern Flow Cytometry Facility, Institutional Animal Care and Use Committee Animal Resources Center, and Animal Research Center. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology, and G.-M.L. holds the Reece A. Overcash Jr. Distinguished Chair for Research on Colon Cancer. We thank Professor David Farrar for providing the CL4 mice, and Drs. Damiana Chiavolini and Jonathan Feinberg for language polishing on the manuscript. This work was supported in part by Cancer Prevention & Research Institute of Texas (CPRIT), United States grants RR150072 and RP180725 to Y.-X.F., RR160101 to G.-M.L, RP190208 To T.W. RP170079 to B.L. Both Y.-X.F. and G.-M.L. are CPRIT Scholars in Cancer Research. B.R. has support from The Swim Across America Foundation Postdoctoral Fellowship. Research was partially supported by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research grant ( SU2C-AACR-DT22-17 ). Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research . This work was also suported by NIH 5P30CA142543 to T.W and 1R01CA245318-01A1 to B.L. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = jan,
day = "11",
doi = "10.1016/j.ccell.2020.11.006",
language = "English (US)",
volume = "39",
pages = "96--108.e6",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}