Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions

BMC Cancer

John M. Pawelek¹  Elham Masoumi²  Mohammad Javad Tavassolifar³  Hosein Rostamian³  Hamid Reza Mirzaei³  Keyvan Fallah-Mehrjardi³  Jamshid Hadjati³  Mohammad Khakpoor-Koosheh³  Leila Jafarzadeh⁴ 

[1] Department of Dermatology and the Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA;Department of Immunology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran;Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;Department of Laboratory Sciences, Sirjan School of Medical Sciences, Sirjan, Iran;

关键词: Metabolism;    Lactic acid;    Cancer;    T cell;    Dichloroacetate, Immunotherapy;   

DOI  :  10.1186/s12885-021-09151-2

来源: Springer

【 摘 要 】

BackgroundLactic 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.ResultWe 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.ConclusionTaken 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.

【 授权许可】

CC BY