Journal
CELL REPORTS
Volume 19, Issue 6, Pages 1189-1201Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.04.031
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Funding
- NIH [R35 CA197633, P01 CA168585, CA-16042, AI-28697]
- Parker Institute for Cancer Immunotherapy
- Dr. Robert Vigen Memorial Fund
- Ressler Family Foundation
- Samuels Family Fund
- Garcia-Corsini Family Fund
- Stand Up To Cancer - Cancer Research Institute Cancer Immunology Dream Team Translational Research [SU2C-AACR-DT1012]
- oncology training grant [5T32CA009297-30]
- dermatology training grant [5T32AR058921-05]
- tumor immunology training grant [5T32CA009120-39]
- Tower Cancer Research Foundation
- Hospital 12 de Octubre, Madrid, Spain [G83727016]
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
- [CURE/P30DK41301-26]
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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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