ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

作者全名："Zhang, Ting; Yin, Chaoran; Fedorov, Aleksandr; Qiao, Liangjun; Bao, Hongliang; Beknazarov, Nazar; Wang, Shiyu; Gautam, Avishekh; Williams, Riley M.; Crawford, Jeremy Chase; Peri, Suraj; Studitsky, Vasily; Beg, Amer A.; Thomas, Paul G.; Walkley, Carl; Xu, Yan; Poptsova, Maria; Herbert, Alan; Balachandran, Siddharth"

作者地址："[Zhang, Ting; Yin, Chaoran; Gautam, Avishekh; Williams, Riley M.; Peri, Suraj; Balachandran, Siddharth] Fox Chase Canc Ctr, Blood Cell Dev & Funct Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA; [Fedorov, Aleksandr; Beknazarov, Nazar; Poptsova, Maria; Herbert, Alan] Natl Res Univ Higher Sch Econ, Fac Comp Sci, Lab Bioinformat, Moscow, Russia; [Qiao, Liangjun] Chongqing Med Univ, Coll Basic Med, Chongqing, Peoples R China; [Bao, Hongliang; Wang, Shiyu; Xu, Yan] Univ Miyazaki, Fac Med, Dept Med Sci, Div Chem, Kiyotake, Miyazaki, Japan; [Crawford, Jeremy Chase; Thomas, Paul G.] St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA; [Studitsky, Vasily] Fox Chase Canc Ctr, Canc Signaling & Epigenet Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA; [Studitsky, Vasily] Lomonosov Moscow State Univ, Biol Fac, Moscow, Russia; [Beg, Amer A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol & Thorac Oncol, Tampa, FL USA; [Walkley, Carl] Univ Melbourne, St Vincents Inst Med Res, St Vincents Hosp, Canc & RNA Biol, Fitzroy, Vic, Australia; [Walkley, Carl] Univ Melbourne, Dept Med, St Vincents Hosp, Fitzroy, Vic, Australia; [Herbert, Alan] InsideOutBio, Charlestown, MA 02129 USA"

通信作者："Balachandran, S (通讯作者)，Fox Chase Canc Ctr, Blood Cell Dev & Funct Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA.; Herbert, A (通讯作者)，Natl Res Univ Higher Sch Econ, Fac Comp Sci, Lab Bioinformat, Moscow, Russia.; Herbert, A (通讯作者)，InsideOutBio, Charlestown, MA 02129 USA."

来源：NATURE

ESI学科分类：Multidisciplinary

WOS号：WOS:000802325500006

JCR分区：Q1

影响因子：64.8

年份：2022

卷号：　

期号：　

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结束页：　

文献类型：Article; Early Access

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摘要："Only a small proportion of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy and prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those arising from the dysregulated expression of endogenous retroviral elements (EREs)(1-4). These dsRNAs trigger an interferon-dependent antitumour response by activating A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR5. Here we show that ADAR1 also prevents the accrual of endogenous Z-form dsRNA elements (Z-RNAs), which were enriched in the 3 ' untranslated regions of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, which culminated in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumour immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily translatable avenue for rekindling the immune responsiveness of ICB-resistant human cancers."

基金机构："NIH [CA168621, CA190542, AI135025, AI144400, GM119398, U01AI150747]; National Health and Medical Research Council, Australia (NHMRC) [APP1144049, APP1183553]; Mark Foundation; American Lebanese Syrian Associated Charities at St Jude Children's Hospital; NIH Cancer Center Support grant [P30CA006927]; Basic Research Program of the National Research University Higher School of Economics"

基金资助正文："We are grateful to E. Gurova for the CBL0137 analogues; M. Bosenberg, J. Upton, A. Degterev and D.R. Green for providing cell lines or antibodies; M. Andrake for help with molecular modelling; and A. Gupte and Z. Liang for technical assistance. This work was supported by a gift from David Wiest and the Seeds of Hope foundation of the Bucks County Board of Associates to S.B., NIH grants CA168621, CA190542, AI135025 and AI144400 to S.B., and NIH grant GM119398 to V.S. C.W. was supported by the National Health and Medical Research Council, Australia (NHMRC; APP1144049 and APP1183553). J.C.C. and P.G.T. were supported by the Mark Foundation, NIH grant U01AI150747, and the American Lebanese Syrian Associated Charities at St Jude Children's Hospital. Additional funds were provided by NIH Cancer Center Support grant P30CA006927 to S.B. A.F., N.B. and M.P. are supported by the Basic Research Program of the National Research University Higher School of Economics, for which A.H. is an International Supervisor."