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

Publication date: 9 May 2017
Source:Cell Reports, Volume 19, Issue 6
Author(s): 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
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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Garcia-Diaz et al. performed a small hairpin RNA screen and genetic and functional studies to map the signaling pathways that result in reactive PD-L1 and PD-L2 on melanoma cells upon interferon gamma exposure. The authors highlight the importance of the JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis for clinical responses to PD-1 blockade therapy.


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