In melanoma and some other cancers, tumor cell PD-1 expression promotes tumorigenesis, and PD-1 blockade limits tumor growth, even in the absence of T cells. Holzgruber, Martins, and Kulcsar found that treatment with IFN-α or IFN-β induced IFNAR-mediated JAK/STAT signaling, which increased chromatin accessibility and STAT1/2 and IRF9 binding within a PD-1 enhancer, leading to upregulation of PD-1 gene expression and protein. Inhibition of IFNAR1 or JAK/STAT suppressed melanoma PD-1 expression and disrupted the efficacy of ICB in mouse models, even in the absence of T cells, suggesting possible contraindications for these drugs in some situations.
Contributed by Lauren Hitchings
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-_ or IFN-_ 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.
Author Info: (1) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Imm
Author Info: (1) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology and Venereology, Medical Faculty, Johannes Kepler University, 4040, Linz, Austria. (2) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. (3) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Center for Skin Diseases, Clinic for Dermatooncology and Phlebology, University Hospital Bonn, 53127, Bonn, Germany. (4) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Centre Hospitalier Universitaire de Bordeaux, Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hpital Saint-Andr, UMR 5164, 33000, Bordeaux, France. (5) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Surgery, University Hospital Mannheim, 68167, Mannheim, Germany. (6) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. (7) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. (8) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. (9) Center for Skin Diseases, Clinic for Dermatooncology and Phlebology, University Hospital Bonn, 53127, Bonn, Germany. (10) CNRS, ImmunoConcEpT, University of Bordeaux, UMR 5164, 33000, Bordeaux, France. (11) Centre Hospitalier Universitaire de Bordeaux, Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hpital Saint-Andr, UMR 5164, 33000, Bordeaux, France. CNRS, ImmunoConcEpT, University of Bordeaux, UMR 5164, 33000, Bordeaux, France. (12) Department of Dermatology and Venereology, Medical Faculty, Johannes Kepler University, 4040, Linz, Austria. (13) Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. (14) Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. (15) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. (16) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. sbarthel@bwh.harvard.edu. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. sbarthel@bwh.harvard.edu. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. sbarthel@bwh.harvard.edu. (17) Department of Dermatology, Brigham and Women's Hospital, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu. Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu. Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu. Department of Medicine, Boston Children's Hospital, Boston, MA, 02115, USA. tschatton@bwh.harvard.edu.
