Gene expression, shRNA, promoter mapping, and CHiP-Seq analysis were used to map the signaling pathways by which exposure to interferons gamma and beta regulate PD-L1 and PD-L2 expression through the JAK/STAT-IRF1 axis and contribute to adaptive immune resistance, providing new therapeutic target and prognostic biomarker opportunities.
PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter. PD-L2 responded equally to interferon beta and gamma and is regulated through both IRF1 and STAT3, which bind to the PD-L2 promoter. Analysis of biopsy specimens from patients with melanoma confirmed interferon signature enrichment and upregulation of gene targets for STAT1/STAT2/STAT3 and IRF1 in anti-PD-1-responding tumors. Therefore, these studies map the signaling pathway of interferon-gamma-inducible PD-1 ligand expression.
Author Info: (1) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Electronic a
Author Info: (1) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Electronic address: agdiaz@ipb.csic.es. (2) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (3) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Division of Translational Oncology, Carlos III Health Institute, 28029 Madrid, Spain. (4) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (5) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (6) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (7) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (8) Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA. (9) Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA. (10) Statistics Core, Department of Medicine, UCLA, Los Angeles, CA 90095, USA. (11) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (12) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (13) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (14) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. (15) Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA. (16) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. (17) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA. (18) Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. (19) Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA. Electronic address: aribas@mednet.ucla.edu.
