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...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
26 August 2024
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| In: |
Nature Communications
Year: 2024, Volume: 15, Pages: 1-16 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-024-51496-2 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-51496-2 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-51496-2 
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| Author Notes: | 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 |
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| 520 | |a 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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