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

Julia Holzgruber; Christina Martins; Zsofi Kulcsar; Alexandra Duplaine; Erik Rasbach; Laure Migayron; Praveen Singh; Edith Statham; Jennifer Landsberg; Katia Boniface; Julien Seneschal; Wolfram Hoetzenecker; Emma L Berdan; Shannan Ho Sui; Matthew R Ramsey; Steven R Barthel; Tobias Schatton

doi:10.1038/s41467-024-51496-2

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.

Authors

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 Landsberg⁵, Katia Boniface⁸, Julien Seneschal^{6

8}, Wolfram Hoetzenecker⁴, Emma L Berdan⁹, Shannan Ho Sui⁹, 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.

MeSH terms

Animals
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Interferon Type I* / metabolism
Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
Interferon-alpha / metabolism
Interferon-alpha / pharmacology
Interferon-beta / metabolism
Janus Kinases / metabolism
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / immunology
Melanoma* / metabolism
Mice
Mice, Inbred C57BL
Programmed Cell Death 1 Receptor* / antagonists & inhibitors
Programmed Cell Death 1 Receptor* / metabolism
Receptor, Interferon alpha-beta* / genetics
Receptor, Interferon alpha-beta* / metabolism
STAT1 Transcription Factor / metabolism
Signal Transduction* / drug effects

Substances

Programmed Cell Death 1 Receptor
Receptor, Interferon alpha-beta
Immune Checkpoint Inhibitors
Interferon Type I
PDCD1 protein, human
IFNAR1 protein, human
STAT1 Transcription Factor
Interferon-Stimulated Gene Factor 3, gamma Subunit
Interferon-beta
IRF9 protein, human
Janus Kinases
STAT1 protein, human
Interferon-alpha

Abstract

MeSH terms

Substances

Grants and funding