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Lactate found to regulate T cell anti-tumour activity

Written by Lauren Robertson, Science Writer

As our understanding of the role of metabolites in the body increases, and as metabolomics technologies continue to improve, their role in regulating the immune system has become a key focus in cancer genomics research. In particular, metabolic reprogramming could offer a potential new avenue for immunotherapy to improve therapeutic outcomes for cancer patients.

To investigate this potential further, researchers have studied the role of lactate in the anti-tumour activity of the immune system. Published in Nature, their paper explores the link between lactate and the “stemness” of CD8+ T cells (their capacity for self-renewal, multipotency, and functional persistence).

Looking at lactate

Lactate, traditionally known as a waste product of carbohydrate fermentation, has recently been identified as a key fuel source for cancer cells and tissues – including immune organs. However, the exact role of lactate in regulating immune cell function has been difficult to elucidate.

Using single-cell transcriptomics, the team discovered that lactate increases the proportion of stem-like TCF-1 CD8+ T cells in the tumour microenvironment. The next question to answer was how exactly lactate was causing this increase.

Besides its role as a fuel source, lactate is also known to function as an agonist to G-protein-coupled receptor (GPCR) signalling and as an inhibitor to histone deacetylase (HDAC). To get a better idea of the exact mechanism behind the increase in TCF-1-expressing T cells, the researchers measured the abundance of around 200 different metabolites. They found that lactate-mediated HDAC inhibition was the most likely potential driver of increased T cell “stemness.”

Figure 4 – Increased stemness of CD8+ T cells in response to lactate. a) Pseudotime analysis showing the differentiation process and distinct “states” of CD8+ T cell subtypes. b) Labelling of top marker genes on pseudotime trajectory show those cells in state 1 are stem-like T cells, while those in state 7 are exhausted T cells. c,d) Change of CD8+ T cell fraction states with lactate treatment. e,f) Flow cytometry plot and quantification of TCF-1 expressions in tumour-infiltrating CD8+ T cells after different treatments.

To further confirm their findings, the team analysed CD3+ T cells from MC38 tumours in mice using single-cell RNA sequencing. They compared the TME after treatment with anti-PD-1 alone or combined with sodium lactate and found that lactate treatment significantly increased the total number of tumour-infiltrating CD8+ T cells by upregulating genes related to their function and signalling pathways.

The future

Overall, lactate seemed to exhibit an immune-protective role in comparison to the immune-suppressive role of lactic acid. The authors conclude that their results “provide evidence for an intrinsic role of lactate in anti-tumour immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.” One suggestion is to use a modified solution with increased lactate concentration to protect CD8+ T cell function during immunotherapy. However, they also highlight the need for more research into the contrasting roles of these two forms of lactate in the future.