Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression
Angel Garcia-Diaz,
Daniel Sanghoon Shin,
Blanca Homet Moreno,
Justin Saco,
Helena Escuin-Ordinas,
Gabriel Abril Rodriguez,
Jesse M. Zaretsky,
Lu Sun,
Willy Hugo,
Xiaoyan Wang,
Giulia Parisi,
Cristina Puig Saus,
Davis Y. Torrejon,
Thomas G. Graeber,
Begonya Comin-Anduix,
Siwen Hu-Lieskovan,
Robert Damoiseaux,
Roger S. Lo,
Antoni Ribas
Affiliations
Angel Garcia-Diaz
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Daniel Sanghoon Shin
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Blanca Homet Moreno
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Justin Saco
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Helena Escuin-Ordinas
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Gabriel Abril Rodriguez
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Jesse M. Zaretsky
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Lu Sun
Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA
Willy Hugo
Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA
Xiaoyan Wang
Statistics Core, Department of Medicine, UCLA, Los Angeles, CA 90095, USA
Giulia Parisi
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Cristina Puig Saus
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Davis Y. Torrejon
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Thomas G. Graeber
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Begonya Comin-Anduix
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA
Siwen Hu-Lieskovan
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
Robert Damoiseaux
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA
Roger S. Lo
Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA
Antoni Ribas
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
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.
