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

Cell Physiol Biochem. 2018;49(2):828-836. doi: 10.1159/000493110. Epub 2018 Aug 30.

Abstract

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.

Keywords: Cytotoxic T lymphocytes; Lactate; Lactate dehydrogenase A; Th1 cells; miR-34a.

MeSH terms

  • 3' Untranslated Regions
  • Base Sequence
  • Case-Control Studies
  • Chromatography, High Pressure Liquid
  • Granzymes / genetics
  • Granzymes / metabolism
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Jurkat Cells
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism*
  • Lactate Dehydrogenase 5
  • Lactates / analysis
  • Lactates / metabolism*
  • Lymphocytes, Tumor-Infiltrating / cytology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Mass Spectrometry
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • 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 / cytology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism

Substances

  • 3' Untranslated Regions
  • Isoenzymes
  • Lactates
  • MIRN34 microRNA, human
  • MicroRNAs
  • Interferon-gamma
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • GZMB protein, human
  • Granzymes