Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression
By A. García-Díaz, D. Shin, B. H. Moreno, Justin Saco, Helena Escuin-Ordinas, G. A. Rodriguez, J. Zaretsky, Lu Sun, Willy Hugo, Xiaoyan Wang and 9 more. Cell Reports, 2017
1,695 citations recorded by the source corpus.
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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/807e1f2da5075638ed79e8a80417fc4f19ba788c
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Citations in the corpus
- SCENIC: Single-cell regulatory network inference and clustering (2017, neutral): “Indeed, a recent study identified the JAK-STAT-IRF axis as driver for the expression of two major targets in immune therapy: PD-L1 and PD-L2; which results in an inhibition of the anti-tumor immune response on the one hand, but an increased response to anti-PD(L)1 immune therapies on the other 80 .”
- Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, background): “of acquired resistance mediated through defective interferon gamma signaling.(25,34) Of note, the one patient with two trans mutations in B2M and loss-of-protein”
- Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma (2019, background): “Interferon-γ signaling has been shown to regulate PD-L1 expression in cancer cells (Chen et al., 2012; Garcia-Diaz et al., 2017), and the combination of increased CD38 protein and mRNA signature (PD-L1, PD-L2, and CTLA4) associated with T cell exhaustion are representative of multiple mechanisms of ”
- Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “Garcia-Diaz et al. have identified two IRF1 binding sites in the PD-L1 promoter region, the abolition of the IRF1 site leads to a reduction in PD-L1 levels [212].”
- Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory (2019, positive): “In vivo, tumor cells can mediate adaptive resistance by upregulating PD-L1 in response to interferon-gamma (IFNγ) released by the cytotoxic T lymphocytes within the tumor bed (Garcia-Diaz et al., 2017).”
- PD-1/PD-L1 pathway: current researches in cancer. (2020, background): “T and NK cells appear to secrete IFN-γ, which induces PD-L1 expression on the surface of the target cells, including tumor cells [23].”
- Mechanisms controlling PD-L1 expression in cancer (2019, positive): “Similarly, several inflammatory cytokines also induce PD-L1 mRNA expression in tumor cells or tumor-associated stromal cells, e.g., TLR3, TNF-α, IFN-α/β, TGF-β, and IL-4/6/17/27 (Carbotti et al., 2015; Garcia-Diaz et al., 2017; M et al., 2016; Ni et al., 2012; Pulko et al., 2009; Quandt et al., 2014”