With continued exposure to tumours, T lymphocytes progressively lose their effectiveness due to the expression of co-inhibitory receptors that act as brakes. Exhausted T lymphocytes, which still retain some anti-cancer function, can deteriorate further until they reach a state of terminal exhaustion. Researchers found that a solute transporter called MCT11, which imports lactic acid, was significantly increased in terminally exhausted T cells compared with their progenitor versions, suggesting that lactic acid contributes to loss of function. When the researchers deleted the gene encoding MCT11 in mice or blocked the protein with a monoclonal antibody, the T cells ingested less lactic acid. They showed improved functionality and tumour control in mouse models of melanoma, colorectal carcinoma and head and neck cancer. The researchers found that the MCT11 antibody promoted tumour killing in mice when administered alone but was even more effective when combined with anti-PD1. Through their new spin-out company, Delgoffe and Peralta are now working to optimise the MCT antibody for efficacy on human T cells to test it in future clinical trials.
