학술논문
Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression.
Document Type
article
Author
Garcia-Diaz, Angel; Shin, Daniel Sanghoon; Moreno, Blanca Homet; Saco, Justin; Escuin-Ordinas, Helena; Rodriguez, Gabriel Abril; Zaretsky, Jesse M; Sun, Lu; Hugo, Willy; Wang, Xiaoyan; Parisi, Giulia; Saus, Cristina Puig; Torrejon, Davis Y; Graeber, Thomas G; Comin-Anduix, Begonya; Hu-Lieskovan, Siwen; Damoiseaux, Robert; Lo, Roger S; Ribas, Antoni
Source
Cell reports. 19(6)
Subject
Language
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.