Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors
Abstract Background 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 incompl...
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2024-10-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-024-02147-z |
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| author | 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 |
| author_facet | 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 |
| author_sort | Clare E. Murray |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| format | Article |
| id | doaj-art-324b033e9fa34bbcab45721b8054a03a |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-324b033e9fa34bbcab45721b8054a03a2025-08-20T02:18:20ZengBMCMolecular Cancer1476-45982024-10-0123112410.1186/s12943-024-02147-zTumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitorsClare E. Murray0Anand V. R. Kornepati1Carlos Ontiveros2Yiji Liao3Bárbara de la Peña Avalos4Cody M. Rogers5Zexuan Liu6Yilun Deng7Haiyan Bai8Suresh Kari9Alvaro S. Padron10Jacob T. Boyd11Ryan Reyes12Curtis A. Clark13Robert S. Svatek14Rong Li15Yanfen Hu16Meiling Wang17José R. Conejo-Garcia18Lauren A. Byers19Kavya Ramkumar20Anil K. Sood21Jung-Min Lee22Christin E. Burd23Ratna K. Vadlamudi24Harshita B. Gupta25Weixing Zhao26Eloïse Dray27Patrick Sung28Tyler J. Curiel29 Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San AntonioDartmouth Cancer Center and Dartmouth Health, Department of Microbiology and Immunology, Geisel School of Medicine at DartmouthDepartment of Biochemistry and Structural Biology, University of Texas Health San AntonioDepartment of Biochemistry and Structural Biology, University of Texas Health San AntonioDepartment of Medicine, University of Texas Health San AntonioDepartment of Medicine, University of Texas Health San AntonioDartmouth Cancer Center and Dartmouth Health, Department of Microbiology and Immunology, Geisel School of Medicine at DartmouthDepartment of Medicine, University of Texas Health San AntonioDepartment of Medicine, University of Texas Health San Antonio Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San AntonioDepartment of Urology, University of Texas Health San AntonioDepartment of Molecular Medicine, University of Texas Health San AntonioDepartment of Molecular Medicine, University of Texas Health San AntonioDepartment of Biochemistry and Structural Biology, University of Texas Health San AntonioDuke Cancer Center, Department of Integrative ImmunobiologyDepartment of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer CenterDepartment of Gynecologic Oncology & Reproductive Medicine, UT MD Anderson Cancer CenterWomen’s Malignancies Branch, Center for Cancer Research, National Cancer InstituteDepartments of Molecular Genetics, Cancer Biology and Genetics, The Ohio State UniversityDepartment of Medicine, University of Texas Health San AntonioDepartment of Biochemistry and Structural Biology, University of Texas Health San AntonioDepartment of Biochemistry and Structural Biology, University of Texas Health San AntonioDepartment of Biochemistry and Structural Biology, University of Texas Health San AntonioDepartment of Biochemistry and Structural Biology, University of Texas Health San Antonio Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San AntonioAbstract Background 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12943-024-02147-zDNA damage repairDDR inhibitorsSynthetic lethalityImmune checkpointsPDL1Chk2 |
| spellingShingle | 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 Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors Molecular Cancer DNA damage repair DDR inhibitors Synthetic lethality Immune checkpoints PDL1 Chk2 |
| title | Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors |
| title_full | Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors |
| title_fullStr | Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors |
| title_full_unstemmed | Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors |
| title_short | Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors |
| title_sort | tumour intrinsic pdl1 signals regulate the chk2 dna damage response in cancer cells and mediate resistance to chk1 inhibitors |
| topic | DNA damage repair DDR inhibitors Synthetic lethality Immune checkpoints PDL1 Chk2 |
| url | https://doi.org/10.1186/s12943-024-02147-z |
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