2. Academic Validation
  3. Synthetic lethal CRISPR screen identifies a cancer cell-intrinsic role of PD-L1 in regulation of vulnerability to ferroptosis

Synthetic lethal CRISPR screen identifies a cancer cell-intrinsic role of PD-L1 in regulation of vulnerability to ferroptosis

  • Cell Rep. 2024 Jul 23;43(7):114477. doi: 10.1016/j.celrep.2024.114477.
Yang-Ying-Fan Feng 1,  Yi-Cun Li 2,  Hai-Ming Liu 1,  Rui Xu 1,  Yu-Tong Liu 1,  Wei Zhang 3,  Hong-Yu Yang 4,  Gang Chen 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
  • 2 Department of Oral and Maxillofacial Surgery, Stomatological Center, Peking University Shenzhen Hospital, Guangdong 518036, China; Guangdong Provincial High-level Clinical Key Specialty, Guangdong 518036, China; Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Guangdong 518036, China; The Institute of Stomatology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong 518036, China.
  • 3 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China. Electronic address: wzhang88@whu.edu.cn.
  • 4 Department of Oral and Maxillofacial Surgery, Stomatological Center, Peking University Shenzhen Hospital, Guangdong 518036, China; Guangdong Provincial High-level Clinical Key Specialty, Guangdong 518036, China; Guangdong Province Engineering Research Center of Oral Disease Diagnosis and Treatment, Guangdong 518036, China; The Institute of Stomatology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Guangdong 518036, China. Electronic address: hyyang192@hotmail.com.
  • 5 State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430079, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China. Electronic address: geraldchan@whu.edu.cn.
PMID: 38985676 DOI: 10.1016/j.celrep.2024.114477
Abstract

Despite the success of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition in tumor therapy, many patients do not benefit. This failure may be attributed to the intrinsic functions of PD-L1. We perform a genome-wide CRISPR synthetic lethality screen to systematically explore the intrinsic functions of PD-L1 in head and neck squamous cell carcinoma (HNSCC) cells, identifying ferroptosis-related genes as essential for the viability of PD-L1-deficient cells. Genetic and pharmacological induction of Ferroptosis accelerates cell death in PD-L1 knockout cells, which are also more susceptible to immunogenic Ferroptosis. Mechanistically, nuclear PD-L1 transcriptionally activates SOD2 to maintain redox homeostasis. Lower Reactive Oxygen Species (ROS) and Ferroptosis are observed in patients with HNSCC who have higher PD-L1 expression. Our study illustrates that PD-L1 confers Ferroptosis resistance in HNSCC cells by activating the SOD2-mediated antioxidant pathway, suggesting that targeting the intrinsic functions of PD-L1 could enhance therapeutic efficacy.

Keywords

CP: Cancer; PD-L1; ROS; SOD2; cell death; ferroptosis; genome-wide CRISPR synthetic lethality screen; immunotherapy; intrinsic function of PD-L1; reactive oxygen species; redox homeostasis.

Figures
Products