Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade PMID: 39187481

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
11. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
12. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].
13. Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].
14. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
15. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].
16. Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. [email protected].
# Contributed equally.

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.