MCT8 modulates metabolite uptake and T cell exhaustion to promote immunosuppression and tumor progression in hepatocellular carcinoma

Abstract Solute carrier family 16 member 2 (SLC16A2), also known as monocarboxylate transporter 8 (MCT8), is a member of the SLC16 family that exerts essential functions in the transport of elemental cell nutrients. This study explores the function of SLC16A2 in hepatocellular carcinoma (HCC) progression, particularly its impact on T cell function. We established Slc16a2 gene knockout (Slc16a2ko) C57BL/6 mice and injected H22 cells subcutaneously to analyze tumor growth and T cell activity in vivo. Additionally, Slc16a2fl/fl mice were crossed with Cd8aCre mice to obtain Slc16a2-Cd8a-ko mice, where Slc16a2 was specifically knocked out in CD8+T cells. In addition to subcutaneous models, luciferase-labeled H22 cells were injected into the liver lobe of mice for orthotopic models. SLC16A2 alteration did not affect proliferation or migration of mouse Hepa1-6 and H22 cells in vitro, though, tumorigenic activity of H22 cells was substantially reduced in Slc16a2ko and Slc16a2-Cd8a-ko C57BL/6 mice. Slc6a2 was highly expressed in Tex cells, and its expression in Tex, as well as the population of Tex cells in tumors, was increased by lactate or other chronic stimuli. An MCT8 monoclonal antibody (mAb) reduced lactate uptake by Tex cells, thus enhancing CD8+ T cell activity and reducing tumor growth in mice. The MCT8 mAb treatment also enhanced the efficacy of anti-PD-L1 in mice bearing tumors. This study supports that SLC16A2 contributes to Tex accumulation in association with increased lactate uptake and hampers immune activity in HCC, supporting SLC16A2 as a promising target to enhance immune activity in HCC management.