Increased Lactate in Gastric Cancer Tumor-Infiltrating Lymphocytes Is Related to Impaired T Cell Function Due to miR-34a Deregulated Lactate Dehydrogenase A

• Published in: Cellular physiology and biochemistry Vol. 49; no. 2; pp. 828 - 836
• Main Authors: Ping, Wang, Senyan, Hu, Li, Gu, Yan, Chen, Long, Lu
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2018; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: 3' Untranslated Regions; Base Sequence; Case-Control Studies; Chromatography, High Pressure Liquid; Cytotoxic T lymphocytes; Dehydrogenases; Gas flow; Gastric cancer; Granzymes - genetics; Granzymes - metabolism; Humans; Immunoglobulins; Interferon-gamma - genetics; Interferon-gamma - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; Jurkat Cells; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; Lactate; Lactate dehydrogenase A; Lactates - analysis; Lactates - metabolism; Lymphocytes; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mass Spectrometry; Metabolism; Metabolites; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-34a; Original Paper; Sequence Alignment; Stomach Neoplasms - diagnosis; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Th1 cells; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; United States > US; China; Germany; Th1 cells; Lactate; miR-34a; Lactate dehydrogenase A; Cytotoxic T lymphocytes
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000493110

Background/Aims: Lactate is one of the products of glycolysis and is a hallmark of the Warburg effect. Glycolysis is found in tumor as well as immune cells. However, the effects of lactate on the function of tumor-infiltrating T cells (TILs) are rarely reported. Methods: In the present study, we investigated lactate and other glycolysis-related metabolites within TILs of human gastric cancer (GC). Lactate concentration was determined by liquid chromatography–mass spectrometry. The functional effects and clinical relevance of excessive lactate on T cells were investigated in clinical samples, and the mechanism of increased lactate was explored. Results: Lactate was significantly increased in GC TILs and related to decreased T helper (Th)1 cells and cytotoxic T lymphocytes (CTLs). Increased lactate within GC TILs was positively correlated with increased lactate dehydrogenase A (LDH)A. Expression of LDHA in GC TILs was also negatively correlated with percentages of Th1 cells and CTLs. Decreased miR-34a expression in GC TILs was responsible for increased expression of LDHA. A hypoxic tumor environment was responsible for decreased miR-34a and lactate-induced impaired immune function. Conclusion: We found that hypoxia decreases miR-34a expression and lose miR-34a regulation on LDHA, thus increasing lactate level within GC TILs and impairing immune function in GC.