Abstract
We investigated whether hypoxia-induced activation of Hh signaling contributes to PDL-1 expression in cancer and whether it affects the anti-tumor function of activated lymphocytes. Hypoxia augmented PDL-1 expression and inhibition of Hh signaling reduced PDL-1 expression under hypoxia. When activated lymphocytes were cocultured with cancers treated with a Hh inhibitor, activated lymphocyte cell numbers increased under hypoxia. In contrast, this increase was abrogated when cancer cells were treated with a PDL-1 neutralizing antibody. These results suggest that Hh signaling is one of regulatory pathways of PDL-1 expression under hypoxia and that inhibiting Hh signaling may induce lymphocyte anti-tumor activity.
Keywords:
Activated lymphocytes; Hedgehog signaling; Hypoxia; PDL-1.
Copyright © 2016 Elsevier Inc. All rights reserved.
MeSH terms
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Antigens, Neoplasm / immunology
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B7-H1 Antigen / genetics
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B7-H1 Antigen / metabolism*
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Cell Line, Tumor
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Coculture Techniques
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Neoplastic
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Hedgehog Proteins / antagonists & inhibitors*
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Humans
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Hypoxia / immunology*
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Hypoxia / therapy
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Lymphocyte Activation
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Lymphocytes / immunology*
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Molecular Targeted Therapy
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Neoplasms / immunology*
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Neoplasms / therapy
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Smoothened Receptor / genetics
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Smoothened Receptor / metabolism
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Trans-Activators
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Veratrum Alkaloids / pharmacology
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Zinc Finger Protein GLI1 / genetics
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Zinc Finger Protein GLI1 / metabolism
Substances
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Antigens, Neoplasm
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B7-H1 Antigen
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DNA-Binding Proteins
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GLI1 protein, human
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Hedgehog Proteins
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MAML3 protein, human
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Nuclear Proteins
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RNA, Small Interfering
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SMO protein, human
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Smoothened Receptor
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Trans-Activators
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Transcription Factors
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Veratrum Alkaloids
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Zinc Finger Protein GLI1
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cyclopamine