International Business Department           Liu Bojia           November 11, 2024

  Among the many characteristics of cancer cells, ‘acidophilia’ is a major concern for oncology researchers. Previous studies have found that under abnormal glycolysis, cancer cells release large amounts of lactic acid, which can be used by themselves, for example, to participate in the inhibition of the p53 protein. At the same time, lactic acid can be released into the tumour microenvironment to build a special barrier for immunosuppression.

  Typically, T cells are exhausted by the constant stimulation of tumour antigens, and some of them are transformed into a state of terminal differentiation depletion, where their self-renewal and effector molecule-releasing capabilities are significantly diminished, and the acid released by the cancer cells is likely to give them a final blow.

  In a recent paper published in Nature Immunology, a team of researchers from the University of Pittsburgh found that when T cells are in an acidic tumour microenvironment, they are forced to take up lactic acid into their cells, further impairing their energy metabolism and lowering intracellular nutrient levels. Analyses of the T cells showed that the more T cells that were heading towards exhaustion, the more likely they were to take up more lactic acid, which accelerated the death of the T cells.

  In addition, the researchers discovered a brand new bright spot when they blocked the lactic acid uptake process in depleted T cells, which began to gradually regain activity and regained control of tumour growth. Professor Greg Delgoffe, corresponding author of the study, pointed out that it is generally assumed that terminally differentiated and depleted T-cells are useless, but the new study proves that they are still useful and the secret is to stop them from taking up lactic acid.

  Although cancer cells are known to secrete lactic acid, the ability of T cells to take up lactic acid is still dependent on their own ‘will’. Therefore, the research team paid special attention to the metabolite transport proteins on the surface of T-cells, which are able to actively exchange lactic acid with their surroundings only if the molecules involved in lactate transport are highly active.

  In their analyses, the solute carrier (SLC) family of proteins caught their particular attention. This is because cancer cells themselves are particularly fond of expressing SLC, which allows them to better translocate nutrients into the cell from the outside, as well as export lactic acid outside the cell. And what is the SLC status of T cells?

  With this question in mind, the team constructed a batch of melanoma mice and collected tumour samples after a period of time, from which they obtained a large number of terminally differentiated depleted T cells. Analyses showed that most of these cells had low levels of SLC on their surface, suggesting that T cells are far weaker than cancer cells when it comes to trophic competition.

  However, very few members of the SLC family appeared highly expressed on failing T cells, the most notable of which was monocarboxylate transporter 11 (MCT11), a protein important for lactate transport. This means that while failing T cells cannot compete for nutrients as well as cancer cells, they are much better at acquiring lactate, which doubles the blow to T cell survival.

  The researchers tried knocking out the MCT11 gene in tumour-bearing mice or blocked its function using an antibody to MCT11, both of which inhibited the lactate transport process of the failing T cells within the tumour. Tumour-bearing mice treated with the MCT11 antibody had their tumour progression significantly controlled, especially when combined with a PD-1 inhibitor, which cleared tumours more effectively.

  The team is now advancing MCT11 antibody-related studies, particularly to determine whether it has a similar role in human failing T cells. The authors note that MCT11 is almost exclusively highly expressed in depleted T cells, which are often found inside tumours, meaning that MCT11 inhibitors would be highly targeted without damaging healthy cells and tissues, making them a highly promising target for cancer therapy.