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

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.