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 () and Tobias Schatton ()
Additional contact information
Julia Holzgruber: Brigham and Women’s Hospital
Christina Martins: Brigham and Women’s Hospital
Zsofi Kulcsar: Brigham and Women’s Hospital
Alexandra Duplaine: Brigham and Women’s Hospital
Erik Rasbach: Brigham and Women’s Hospital
Laure Migayron: Brigham and Women’s Hospital
Praveen Singh: Brigham and Women’s Hospital
Edith Statham: Brigham and Women’s Hospital
Jennifer Landsberg: University Hospital Bonn
Katia Boniface: University of Bordeaux, UMR 5164
Julien Seneschal: UMR 5164
Wolfram Hoetzenecker: Johannes Kepler University
Emma L. Berdan: Harvard T.H. Chan School of Public Health
Shannan Ho Sui: Harvard T.H. Chan School of Public Health
Matthew R. Ramsey: Brigham and Women’s Hospital
Steven R. Barthel: Brigham and Women’s Hospital
Tobias Schatton: Brigham and Women’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-51496-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51496-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-51496-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().