Journal Article

ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

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

2022

Overview

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 PKR 5 . 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. A small molecule can bypass the RNA-editing enzyme ADAR1 to directly activate the Z-form nucleic acid sensor ZBP1, induce necroptosis in tumour fibroblasts and reverse resistance to immune checkpoint blockade in mouse models of melanoma.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/2 / 13/95 / 14 / 14/19 / 3' Untranslated Regions / 45 / 45/15 / 45/77 / 45/91 / 631/250/1933 / 631/67/1059/2325 / 82 / 82/29 / 96 / 96/34 / 96/63 / Ablation / Adenosine / Adenosine Deaminase - metabolism / Animal models / Animals / Antibodies / Cancer / Cancer-Associated Fibroblasts / Carbazoles - pharmacology / CRISPR / Depletion / DNA structure / Double-stranded RNA / Enzymes / Fibroblasts / Humanities and Social Sciences / Humans / Immune checkpoint / Immunogenicity / Immunotherapy - trends / Interferon / Interferons - metabolism / Kinases / Melanoma / Mice / multidisciplinary / Mutation / Necroptosis / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Proteins / Ribonucleic acid / RNA / RNA editing / RNA, Double-Stranded - immunology / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Sensors / Z-form