Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling

• Published in: Science China. Life sciences Vol. 59; no. 12; pp. 1290 - 1296
• Main Authors: Xie, Di, Zhu, Shasha, Bai, Li
• Format: Journal Article
• Language: English
• Published: Beijing Science China Press 01.12.2016; Springer Nature B.V
• Subjects: Active Transport, Cell Nucleus - drug effects; Animals; Biomedical and Life Sciences; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Flow Cytometry; Humans; Hydrogen-Ion Concentration; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Kruppel-Like Transcription Factors - metabolism; Lactic Acid - metabolism; Lactic Acid - pharmacology; Life Sciences; Mice, Transgenic; Microscopy, Confocal; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - metabolism; Neoplasms - metabolism; Neoplasms - pathology; Promyelocytic Leukemia Zinc Finger Protein; Research Paper; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Tumor Microenvironment; lactic acid; IFNγ; mTOR; NKT cell; PLZF
• ISSN: 1674-7305; 1869-1889
• DOI: 10.1007/s11427-016-0348-7

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 IFN？ and IL4 productions from NKT cells, and more profound influence on IFN？ was observed. By adjusting the pH of culture medium we fiu-ther 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 （roTOR） 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.