Lactic acid is one of the metabolic waste products that cancer cells release into the surrounding environment as they proliferate. According to recent research from the University of Pittsburgh and UPMC Hillman Cancer Center, exhausted T cells that have lost their ability to fight cancer eat this lactic acid, which further depletes their vitality.
Exhausted T cells were given a new lease on life when the researchers blocked the protein that imports lactic acid into cells. This boosted tumor control in cancer mice models.
New findings were published in the journal Nature Immunology.
Blocking access to inhibitory metabolites is a completely new take on how we can reinvigorate the immune system,
We often think of exhausted T cells being useless, but this study shows that we can actually get juice out of these cells by blocking negative effects of the tumor microenvironment.
Greg Delgoffe
T cells gradually lose their effectiveness when exposed to tumors repeatedly because they express coinhibitory receptors, which function as brakes. Terminally exhausted T cells can develop from progenitor-fatigued T cells, which still have some capacity to destroy cancer. By inhibiting coinhibitory receptors, the majority of immunotherapies, such as the checkpoint inhibitor medications anti-PD1 and anti-CTLA4, try to release these brakes.
Checkpoint inhibitors, which are the main weapons in our immunotherapy arsenal, have been incredibly successful for some patients with certain cancers, but there have also been a lot of failures, and they haven’t been the gamechangers we expected in many cancers,
There’s only so much you can do by taking your foot off the brake.
Greg Delgoffe
Delgoffe and lead author Ronal Peralta, Ph.D., a postdoctoral associate in Delgoffe’s lab, began their search for novel approaches to rejuvenate fatigued T cells by examining a class of proteins known as solute carriers, which carry nutrients into cells,
Exhausted T cells have been studied extensively in terms of what they can no longer do exhausted T cells have been studied extensively in terms of what they can no longer do,
But what do exhausted T cells do? What do they eat? What nutrients do they have access to? These questions were the starting point of our study.
Ronal Peralta
Peralta discovered that terminally fatigued T cells had significantly higher levels of a solute carrier termed MCT11, which imports lactic acid, than their progenitor counterparts. This finding suggests that lactic acid plays a role in the loss of function.
T cells consumed less lactic acid and demonstrated enhanced functioning and tumor control in animal models of melanoma, colorectal carcinoma, and head and neck cancer when he eliminated the gene expressing MCT11 in mice or inhibited the protein using a monoclonal antibody.
Peralta discovered that terminally fatigued T cells had significantly higher levels of a solute carrier termed MCT11, which imports lactic acid, than their progenitor counterparts. This finding suggests that lactic acid plays a role in the loss of function.
T cells consumed less lactic acid and demonstrated enhanced functioning and tumor control in animal models of melanoma, colorectal carcinoma, and head and neck cancer when he eliminated the gene expressing MCT11 in mice or inhibited the protein using a monoclonal antibody. Similar to how blocking MCT11 prevents T cells from accessing lactic acid, which hinders their activity, the automobile has better access to gas that improves its performance.
When we get rid of MCT11, there’s no difference in the expression of coinhibitory receptors on T cells,
They’re still technically exhausted, but they behave as functional T cells because we cut off the tap of this bad metabolite: lactic acid.
Greg Delgoffe
When administered alone, the MCT11 antibody helped mice’s tumors to be cleared, but when paired with anti-PD1, the researchers observed significantly greater efficacy.
In order to test the MCT antibody in upcoming clinical trials, Delgoffe and Peralta are currently attempting to improve it for efficacy in human T cells through their new spinout company.
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Peralta claims that because MCT11 is nearly solely expressed in worn-out T cells, which are primarily seen in malignancies, it is a desirable therapeutic target. This suggests that medications that target MCT11 may be less likely to have adverse effects than more conventional immunotherapies like anti-PD-1, which affect T cells all across the body.
This research is really exciting because it’s proof-of-concept that targeting how T cells interact with metabolites in their environment can promote better outcomes in cancer,
It opens the door for exploring how we can go after other targets in immune cells for treating cancer and many other diseases.
Ronal Peralta
Source: UPMC – News
Journal Reference: Peralta, Ronal M., et al. “Dysfunction of Exhausted T Cells Is Enforced by MCT11-mediated Lactate Metabolism.” Nature Immunology, 2024, pp. 1-11, DOI: https://doi.org/10.1038/s41590-024-01999-3.
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