Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors
Authors
Clare E. Murray, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Anand V. Kornepati, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Carlos Ontiveros, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Yiji Liao, Dartmouth Cancer Center and Dartmouth Health, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Bárbara de la Peña Avalos, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
Cody M. Rogers, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
Zexuan Liu, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Yilun Deng, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Haiyan Bai, Dartmouth Cancer Center and Dartmouth Health, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Suresh Kari, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Alvaro S. Padron, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Jacob T. Boyd, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Ryan Reyes, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Curtis A. Clark, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Robert S. Svatek, Department of Urology, University of Texas Health San Antonio, San Antonio, TX, USA.
Rong Li, Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Yanfen Hu, Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Meiling Wang, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
José R. Conejo-Garcia, Duke Cancer Center, Department of Integrative Immunobiology, Durham, NC, USA.
Lauren A. Byers, Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kavya Ramkumar, Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Anil K. Sood, Department of Gynecologic Oncology & Reproductive Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
Jung-Min Lee, Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Christin E. Burd, Departments of Molecular Genetics, Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
Ratna K. Vadlamudi, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Harshita B. Gupta, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
Weixing Zhao, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
Eloïse Dray, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
Patrick Sung, Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
Tyler J. Curiel, Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA. tyler.j.curiel@dartmouth.edu.
Document Type
Journal Article
Publication Date
10-30-2024
DOI
10.1186/s12943-024-02147-z
Keywords
Chk2; DDR inhibitors; DNA damage repair; Immune checkpoints; PDL1; Synthetic lethality
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.
APA Citation
Murray, Clare E.; Kornepati, Anand V.; Ontiveros, Carlos; Liao, Yiji; de la Peña Avalos, Bárbara; Rogers, Cody M.; Liu, Zexuan; Deng, Yilun; Bai, Haiyan; Kari, Suresh; Padron, Alvaro S.; Boyd, Jacob T.; Reyes, Ryan; Clark, Curtis A.; Svatek, Robert S.; Li, Rong; Hu, Yanfen; Wang, Meiling; Conejo-Garcia, José R.; Byers, Lauren A.; Ramkumar, Kavya; Sood, Anil K.; Lee, Jung-Min; Burd, Christin E.; Vadlamudi, Ratna K.; Gupta, Harshita B.; Zhao, Weixing; Dray, Eloïse; Sung, Patrick; and Curiel, Tyler J., "Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors" (2024). GW Authored Works. Paper 5755.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/5755
Department
Biochemistry and Molecular Medicine
