Wang Ping1, Hu Senyan2, Gu Li1, Chen Yan1, Lu Long2,3. 1. Department of Endocrinology, People's Hospital of Gaochun, Nanjing, China. 2. Department of Surgery, People's Hospital of Gaochun, Nanjing, China. 3. Department of Surgery, Nanjing Jiangbei People's Hospital, Nanjing, China.
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.
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 humangastric 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.