肿瘤内在的 PDL1 信号调控癌细胞中的 Chk2 DNA 损伤反应,并介导对 Chk1 抑制剂的耐药性

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Clare E. Murray, Anand V. R. Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara de la Peña Avalos, Cody M. Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S. Padron, Jacob T. Boyd, Ryan Reyes, Curtis A. Clark, Robert S. Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R. Conejo-Garcia, Lauren A. Byers, Kavya Ramkumar, Anil K. Sood, Jung-Min Lee, Christin E. Burd, Ratna K. Vadlamudi, Harshita B. Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel
{"title":"肿瘤内在的 PDL1 信号调控癌细胞中的 Chk2 DNA 损伤反应,并介导对 Chk1 抑制剂的耐药性","authors":"Clare E. Murray, Anand V. R. Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara de la Peña Avalos, Cody M. Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S. Padron, Jacob T. Boyd, Ryan Reyes, Curtis A. Clark, Robert S. Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R. Conejo-Garcia, Lauren A. Byers, Kavya Ramkumar, Anil K. Sood, Jung-Min Lee, Christin E. Burd, Ratna K. Vadlamudi, Harshita B. Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel","doi":"10.1186/s12943-024-02147-z","DOIUrl":null,"url":null,"abstract":"Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"5 1","pages":""},"PeriodicalIF":27.7000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors\",\"authors\":\"Clare E. Murray, Anand V. R. Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara de la Peña Avalos, Cody M. Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S. Padron, Jacob T. Boyd, Ryan Reyes, Curtis A. Clark, Robert S. Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R. Conejo-Garcia, Lauren A. Byers, Kavya Ramkumar, Anil K. Sood, Jung-Min Lee, Christin E. Burd, Ratna K. Vadlamudi, Harshita B. Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J. Curiel\",\"doi\":\"10.1186/s12943-024-02147-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.\",\"PeriodicalId\":19000,\"journal\":{\"name\":\"Molecular Cancer\",\"volume\":\"5 1\",\"pages\":\"\"},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12943-024-02147-z\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12943-024-02147-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

除了 PDL1 作为肿瘤表面表达的免疫检查点分子的典型作用外,肿瘤内在 PDL1 信号还调节介导治疗耐药性的非典型免疫病理通路,而这些通路的意义、机制和治疗靶点仍不完全清楚。最近有报道称,肿瘤内在的PDL1信号与DNA损伤应答(DDR)有关,包括促进同源重组DNA损伤修复和DDR蛋白的mRNA稳定性,但许多机制细节仍未确定。我们从可移植的小鼠和人类癌细胞系中基因删除了 PDL1,以了解 DNA 损伤反应中肿瘤内在 PDL1 信号的后果。我们还对原发性人类肿瘤和诱导性小鼠肿瘤进行了研究。我们开发了新方法来显示特定亚细胞位置的肿瘤内在 PDL1 信号。我们在小鼠模型中使用美国食品药物管理局批准的再利用药物对肿瘤 PDL1 进行体内药理学耗竭,以进行概念验证临床转化研究。我们发现,肿瘤内在的 PDL1 可促进检查点激酶-2(Chk2)介导的 DNA 损伤反应。细胞内而非表面表达的PDL1通过拮抗PIRH2 E3连接酶介导的Chk2多泛素化和蛋白降解,在翻译后控制Chk2蛋白含量,且独立于PD1。遗传性肿瘤 PDL1 基因耗竭特异性地降低了肿瘤 Chk2 的含量,但没有降低 ATM、ATR 或 Chk1 DDR 蛋白的含量,增强了 Chk1 抑制剂(Chk1i)在多种人类和鼠类肿瘤模型中的体外合成致死率,并提高了 Chk1i 在体内的疗效。用头孢吡肟或头孢唑肟对肿瘤 PDL1 进行药理耗竭可复制遗传性肿瘤 PDL1 耗竭,减少肿瘤 Chk2,以肿瘤 PDL1 依赖性方式诱导 Chk1i 合成致死,并在与 Chk1i 联用时减少体内肿瘤生长。我们的数据对目前流行的表面 PDL1 范式提出了挑战,阐明了肿瘤内在 PDL1 在调节 ATM/Chk2 DNA 损伤反应轴和 E3 连接酶介导的蛋白质降解方面的重要作用,建议将肿瘤 PDL1 作为 Chk1i 疗效的生物标记物,并支持药物性肿瘤 PDL1 消减治疗特定癌症的快速临床潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors
Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined. We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours and inducible mouse tumours. We developed novel approaches to show tumour-intrinsic PDL1 signals in specific subcellular locations. We pharmacologically depleted tumour PDL1 in vivo in mouse models with repurposed FDA-approved drugs for proof-of-concept clinical translation studies. We show that tumour-intrinsic PDL1 promotes the checkpoint kinase-2 (Chk2)-mediated DNA damage response. Intracellular but not surface-expressed PDL1 controlled Chk2 protein content post-translationally and independently of PD1 by antagonising PIRH2 E3 ligase-mediated Chk2 polyubiquitination and protein degradation. Genetic tumour PDL1 depletion specifically reduced tumour Chk2 content but not ATM, ATR, or Chk1 DDR proteins, enhanced Chk1 inhibitor (Chk1i) synthetic lethality in vitro in diverse human and murine tumour models, and improved Chk1i efficacy in vivo. Pharmacologic tumour PDL1 depletion with cefepime or ceftazidime replicated genetic tumour PDL1 depletion by reducing tumour Chk2, inducing Chk1i synthetic lethality in a tumour PDL1-dependent manner, and reducing in vivo tumour growth when combined with Chk1i. Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信