Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.
BMC Cancer
; 22(1): 39, 2022 Jan 06.
Article
em En
| MEDLINE
| ID: mdl-34991504
ABSTRACT
BACKGROUND:
Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells.RESULT:
We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis.CONCLUSION:
Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ativação Linfocitária
/
Linfócitos T
/
Ácido Láctico
/
Ácido Dicloroacético
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article