MCT1/4 and CD147 in cancer immunosurveillance: new tools for T-cell based immunotherapy?
Monocarboxylate transporters (MCTs) 1 and 4 are transmembrane proteins upregulated in cancer cells, playing an important role in the efflux of proton-coupled lactate derived from glycolysis. These transporters require an accessory protein known as CD147 for a proper expression and activity in the plasma membrane. CD147 is a widely expressed transmembrane glycoprotein shown to be enriched on tumor cell surface and to be associated with tumor invasion, metastasis and angiogenesis. Preliminary studies suggested the involvement of MCT1/4 as well as their chaperone CD147 in tumor immunosuppression. These transmembrane proteins were shown to regulate the crosstalk between tumor and tumor-infiltrating immune cells, re-educate them into a pro-tumoral phenotype and promote an immunosuppressive tumor microenvironment (TME) that may confer immunotherapeutic resistance. Immune-checkpoint blockade targeting programed cell death-1/PD-1 ligand (PD-1/PD-L1) has revolutionized cancer therapy. Despite PD-1/PD-L1 inhibition as a monotherapy has resulted in remarkable therapeutic responses, a significant portion of patients remains unresponsive. Therefore, it is crucial to develop combinatorial approaches targeting multiple immune inhibitory mechanisms. Thus, using in vitro and in vivo approaches, we intend to dissect the biological mechanisms in which MCT1/4 and CD147 induce TME immunosuppression and provide new tools to improve anti-PD-1 immunotherapy.