Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression

Ángel García-Díaz(University of California, Los Angeles), Daniel Sanghoon Shin(University of California, Los Angeles), Blanca Homet Moreno(University of California, Los Angeles), Justin D. Saco(University of California, Los Angeles), Helena Escuin-Ordinas(University of California, Los Angeles), Gabriel Abril Rodriguez(University of California, Los Angeles), Jesse M. Zaretsky(University of California, Los Angeles), Lu Sun(University of California, Los Angeles), Willy Hugo(University of California, Los Angeles), Xiaoyan Wang(University of California, Los Angeles), Giulia Parisi(University of California, Los Angeles), Cristina Puig-Saus(University of California, Los Angeles), Davis Y. Torrejon(University of California, Los Angeles), Thomas G. Graeber(UCLA Medical Center), Begonya Comin-Anduix(University of California, Los Angeles), Siwen Hu‐Lieskovan(University of California, Los Angeles), Robert Damoiseaux(California NanoSystems Institute), Roger S. Lo(University of California, Los Angeles), Antoni Ribas(University of California, Los Angeles)
Cell Reports
May 1, 2017
10.1016/j.celrep.2017.04.031
Cited by 1,898Open Access
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Abstract

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.

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