title: Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling.
abstract: Cellular metabolism has been shown to regulate differentiation and function of immune cells. Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments. NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials. However, the influences of tumor microenvironments on NKT cell functions remain unclear. In our studies, lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells, and more profound influence on IFNγ was observed. By adjusting the pH of culture medium we further showed that, dysfunction of NKT cells could simply be induced by low extracellular pH. Moreover, low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin (mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger (PLZF). Together, our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.
authors.affiliation: CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.|Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China.
authors.forename: Di
authors.initials: D
authors.lastname: Xie
authors.affiliation: CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.|Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhu
authors.affiliation: CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China. baili@ustc.edu.cn.|Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China. baili@ustc.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse; D015847:Interleukin-4; D019344:Lactic Acid; D007371:Interferon-gamma; D058570:TOR Serine-Threonine Kinases
keywords: IFNγ; NKT cell; PLZF; lactic acid; mTOR