2. Academic Validation
  3. Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade

Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade

  • Nat Commun. 2024 Aug 26;15(1):7165. doi: 10.1038/s41467-024-51496-2.
Julia Holzgruber # 1 2 3 4,  Christina Martins # 1 2 3,  Zsofi Kulcsar # 1 2 3 5,  Alexandra Duplaine 1 2 6,  Erik Rasbach 1 2 3 7,  Laure Migayron 1 2 3,  Praveen Singh 1 2 3,  Edith Statham 1 2,  Jennifer Landsberg 5,  Katia Boniface 8,  Julien Seneschal 6 8,  Wolfram Hoetzenecker 4,  Emma L Berdan 9,  Shannan Ho Sui 9,  Matthew R Ramsey 1 2,  Steven R Barthel 10 11 12,  Tobias Schatton 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • 2 Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA.
  • 3 Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • 4 Department of Dermatology and Venereology, Medical Faculty, Johannes Kepler University, 4040, Linz, Austria.
  • 5 Center for Skin Diseases, Clinic for Dermatooncology and Phlebology, University Hospital Bonn, 53127, Bonn, Germany.
  • 6 Centre Hospitalier Universitaire de Bordeaux, Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hôpital Saint-André, UMR 5164, 33000, Bordeaux, France.
  • 7 Department of Surgery, University Hospital Mannheim, 68167, Mannheim, Germany.
  • 8 CNRS, ImmunoConcEpT, University of Bordeaux, UMR 5164, 33000, Bordeaux, France.
  • 9 Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
  • 10 Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. sbarthel@bwh.harvard.edu.
  • 11 Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. sbarthel@bwh.harvard.edu.
  • 12 Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. sbarthel@bwh.harvard.edu.
  • 13 Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu.
  • 14 Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu.
  • 15 Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu.
  • 16 Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu.
  • # Contributed equally.
PMID: 39187481 DOI: 10.1038/s41467-024-51496-2
Abstract

Programmed cell death 1 (PD-1) is a premier Cancer drug target for Immune Checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, Cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-β triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of Cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.

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