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

• Published in: Cell reports (Cambridge) Vol. 19; no. 6; pp. 1189 - 1201
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.05.2017; Elsevier
• Subjects: B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; immunotherapy; interferon receptor signaling pathways; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Interferon-beta - metabolism; Interferon-gamma - metabolism; IRF1; JAK-STATs; Janus Kinase 1 - metabolism; Janus Kinase 2 - metabolism; melanoma; Melanoma - genetics; Melanoma - metabolism; PD-1; PD-L1; PD-L2; Programmed Cell Death 1 Ligand 2 Protein - genetics; Programmed Cell Death 1 Ligand 2 Protein - metabolism; Promoter Regions, Genetic; Protein Binding; Signal Transduction; STAT Transcription Factors - metabolism; Transcriptional Activation; Up-Regulation; IRF1; immunotherapy; PD-L1; PD-L2; melanoma; interferon receptor signaling pathways; JAK-STATs; PD-1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.04.031

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. [Display omitted] •PD-L1 is primarily regulated by interferon gamma signaling in melanoma cells•PD-L2 is regulated by both interferon beta and gamma signaling•Regulation of PD-1 ligands works mainly through the JAK1/2-STAT1/3-IRF1 axis 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.