title: Hedgehog signaling regulates PDL-1 expression in cancer cells to induce anti-tumor activity by activated lymphocytes.
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.
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: ohnishi@surg1.med.kyushu-u.ac.jp.
authors: Hideya
authors: H
authors: Onishi
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Akiko
authors: A
authors: Fujimura
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yasuhiro
authors: Y
authors: Oyama
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Akio
authors: A
authors: Yamasaki
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Shukoukai Inc., Tokyo, Japan.
authors: Akira
authors: A
authors: Imaizumi
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Makoto
authors: M
authors: Kawamoto
authors: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Mitsuo
authors: M
authors: Katano
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Masayo
authors: M
authors: Umebayashi
authors: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors: Takashi
authors: T
authors: Morisaki
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000072086:Smoothened Receptor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; D004268:DNA-Binding Proteins; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C471298:MAML3 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine
keywords: Activated lymphocytes; Hedgehog signaling; Hypoxia; PDL-1