Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade
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.
Authors
- Jennifer Landsberg (ORCID: https://orcid.org/0000-0001-8029-3883)
- Christina Martins (ORCID: https://orcid.org/0000-0002-9160-1017)
- Edith Statham (ORCID: https://orcid.org/0009-0004-9798-5930)
- Laure Migayron (ORCID: https://orcid.org/0000-0003-2003-1923)
- Katia Boniface (ORCID: https://orcid.org/0000-0003-4428-1222)
- Wolfram Hoetzenecker (ORCID: https://orcid.org/0000-0003-4710-0642)
- Steven R. Barthel (ORCID: https://orcid.org/0000-0003-2107-4570)
- Emma L. Berdan (ORCID: https://orcid.org/0000-0002-6435-4604)
- Alexandra Duplaine
- Erik Rasbach (ORCID: https://orcid.org/0000-0002-0807-3058)
- Tobias Schatton (ORCID: https://orcid.org/0000-0003-1386-680X)
- Matthew R. Ramsey (ORCID: https://orcid.org/0000-0003-2402-8502)
- Julien Sénéschal (ORCID: https://orcid.org/0000-0003-1139-0908)
- Julia Holzgruber (ORCID: https://orcid.org/0000-0002-7804-9387)
- Praveen Kumar Singh (ORCID: https://orcid.org/0000-0002-8188-2636)
- Zsófi Kulcsár
- Shannan Ho Sui
Institutions
- Johannes Kepler University of Linz (AT)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Université de Bordeaux (FR)
- Heidelberg University (DE)
- University Hospital Bonn (DE)
- University Hospital Heidelberg (DE)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Hôpital Saint-André (FR)
- Immunology from Concept and Experiments to Translation (FR)
- University Medical Centre Mannheim (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1038/s41467-024-51496-2
- Citations
- 42
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 11.87
Funders
- American Skin Association
- Brigham and Women's Hospital
- European Academy of Dermatology and Venereology
- National Institutes of Health
- Harvard Stem Cell Institute
- Brigham Research Institute
- National Cancer Institute