[PDF][PDF] Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression

A Garcia-Diaz, DS Shin, BH Moreno, J Saco… - Cell reports, 2017 - cell.com
A Garcia-Diaz, DS Shin, BH Moreno, J Saco, H Escuin-Ordinas, GA Rodriguez, JM Zaretsky
Cell reports, 2017cell.com
Summary 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 …
Summary
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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