Abstract
Monocarboxylate transporter‐4 (MCT4), a monocarboxylic acid transporter, demonstrates significantly increased expression in the majority of malignancies. We performed an experiment using BALB/C mice, and our results showed that ShMCT4 transfection or the pharmaceutic inhibition of MCT4 with 7acc1 strengthens the activity of NK cells. The results of a calcein assay revealed that the cytotoxicity of NK cells was strengthened via inhibition of MCT4. In addition, ELISA testing showed that the content of perforin and CD107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG2D and H60 was upregulated after the inhibition of MCT4. Further, we observed an elevated pH value, decreased extracellular lactate flow, and attenuated tumor growth. Therefore, we concluded that the inhibition of MCT4 enhanced the cytotoxicity of NK cells by blocking lactate flux and reversing the acidified tumor microenvironment. In addition to these findings, we also discovered that MCT4 depletion may have a pronounced impact on autophagy, which was surmised by observing that the inhibition of autophagy (3MA) pulled the enhanced cytotoxicity of NK cells downwards. Together, these data suggest that the key effect of MCT4 depletion on NK cells probably utilizes inductive autophagy as a compensatory metabolic mechanism to minimize the acidic extracellular microenvironment associated with lactate export in tumors.
Highlights
Glycolysis produces abundant lactic acid as the main method of harvesting energy, which enables malignant tumor cells to survive in anoxic microenvironments.[1,2] Because decreasing the extracellular pH changes the immune phenotype and disturbs the immune function of tumor infiltrating lymphocytes, the enhanced lactic acid is more conducive to tumor immune escape and invasion.[3-7]
Because Monocarboxylate transporter-4 (MCT4) has the capacity to alter the microenvironment in tumors, we felt we had a compelling reason to investigate the effect of MCT4 on NK cells
We demonstrated how MCT4 effectively influences the concentration of lactate and the cytotoxicity of NK cells
Summary
Glycolysis produces abundant lactic acid as the main method of harvesting energy, which enables malignant tumor cells to survive in anoxic microenvironments.[1,2] Because decreasing the extracellular pH (pHe) changes the immune phenotype and disturbs the immune function of tumor infiltrating lymphocytes, the enhanced lactic acid is more conducive to tumor immune escape and invasion.[3-7]. The blockade of MCT4 expression has been shown to represent a novel treatment target in glioblastoma, large B-c ell lymphoma, and multiple myeloma.[25-27]. For these reasons, and because MCT4 has the capacity to alter the microenvironment in tumors, we felt we had a compelling reason to investigate the effect of MCT4 on NK cells. Our study offered some important insight into the distribution of activated NK cells in human breast cancer tissues and provided an opportunity to further exploit the function of MCT4 on the lactic acid concentration and the cytotoxicity of NK cells in vitro and in vivo. We demonstrated how MCT4 effectively influences the concentration of lactate and the cytotoxicity of NK cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
