2. Academic Validation
  3. Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors

Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors

  • Mol Cancer. 2024 Oct 30;23(1):242. doi: 10.1186/s12943-024-02147-z.
Clare E Murray # 1,  Anand V R Kornepati # 1 2,  Carlos Ontiveros 1,  Yiji Liao 3,  Bárbara de la Peña Avalos 4,  Cody M Rogers 4,  Zexuan Liu 5,  Yilun Deng 5,  Haiyan Bai 3,  Suresh Kari 5,  Alvaro S Padron 5,  Jacob T Boyd 1,  Ryan Reyes 1,  Curtis A Clark 1 6,  Robert S Svatek 7 8,  Rong Li 9 10,  Yanfen Hu 9 11,  Meiling Wang 4,  José R Conejo-Garcia 12,  Lauren A Byers 13,  Kavya Ramkumar 13,  Anil K Sood 14,  Jung-Min Lee 15,  Christin E Burd 16,  Ratna K Vadlamudi 5 8,  Harshita B Gupta 4,  Weixing Zhao 4,  Eloïse Dray 4,  Patrick Sung 4 8,  Tyler J Curiel 17 18 19 20 21 22 23 24
Affiliations

Affiliations

  • 1 Graduate School of Biomedical Sciences and Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 2 Present address: Department of Internal Medicine, New York University Grossman School of Medicine, New York, NY, USA.
  • 3 Dartmouth Cancer Center and Dartmouth Health, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • 4 Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 5 Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 6 Present address: Department of Radiation Oncology, School of Medicine, University of Alabama Birmingham, Birmingham, USA.
  • 7 Department of Urology, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 8 UT Health Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 9 Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 10 Present address: Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC, USA.
  • 11 Present address: Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, DC, USA.
  • 12 Duke Cancer Center, Department of Integrative Immunobiology, Durham, NC, USA.
  • 13 Department of Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 14 Department of Gynecologic Oncology & Reproductive Medicine, UT MD Anderson Cancer Center, Houston, TX, USA.
  • 15 Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 16 Departments of Molecular Genetics, Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
  • 17 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.
  • 18 Dartmouth Cancer Center and Dartmouth Health, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. tyler.j.curiel@dartmouth.edu.
  • 19 Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA. tyler.j.curiel@dartmouth.edu.
  • 20 UT Southwestern, Dallas, TX, USA. tyler.j.curiel@dartmouth.edu.
  • 21 Dartmouth Health and Dartmouth Cancer Center, Lebanon, NH, USA. tyler.j.curiel@dartmouth.edu.
  • 22 The Geisel School of Medicine at Dartmouth, Hanover, NH, USA. tyler.j.curiel@dartmouth.edu.
  • 23 Department of Immunology, Dartmouth College, Hanover, NH, USA. tyler.j.curiel@dartmouth.edu.
  • 24 Department of Integrative Immunobiology, Duke University, Durham, NC, USA. tyler.j.curiel@dartmouth.edu.
  • # Contributed equally.
PMID: 39478560 DOI: 10.1186/s12943-024-02147-z
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.

Keywords

Chk2; DDR inhibitors; DNA damage repair; Immune checkpoints; PDL1; Synthetic lethality.

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