Continuous metabolism of glucose to lactate by tumour cells, through upregulation of glycolytic enzymes, such as lactate dehydrogenase A (LDHA), creates a tumour microenvironment rich in lactic acid. Previous studies have suggested a correlation between increased lactate production and tumour progression. Now, Brand et al. report that lactic acid accumulation by highly glycolytic tumours is a strategy for immune evasion, thereby affording the tumour a growth advantage.
To investigate whether lactic acid could compromise tumour immunosurveillance, the authors used a melanoma model to compare the growth rate of mouse melanoma B16.SIY cells with reduced levels of Ldha (LDHAlow) in immunocompetent (C57BL/6) versus immunodeficient (Rag2−/−γc−/−) mice. LDHAlow tumours, which secreted less lactate, grew at a slower rate and with increased infiltration of T cells and natural killer (NK) cells in immunocompetent mice than those of control tumours (formed from B16.SIY cells with comparatively higher levels of Ldha expressed). By contrast, in Rag2−/−γc−/− mice, which lack B, T and NK cells, LDHAlow and control tumours developed at the same rate, indicating that immune cell infiltration in LDHAlow tumours is effective at limiting tumour expansion. Interestingly, this effect of tumour-induced lactic acid production on the immune cell balance seems to be restricted to the local tumour environment as the composition of immune cells in the blood and spleen of LDHAlow tumour-bearing mice was unchanged.
tumour-derived lactic acid could perturb cytokine production of tumour-infiltrating T and NK cells
Brand et al. identified the tumour immune infiltrate in LDHAlow tumours as containing a higher proportion of CD8+ T cells and NK cells, with both effector cell types expressing increased levels of interferon-γ (IFN-γ, encoded by Ifng). Moreover, IFN-γ production was necessary for the control of LDHAlow tumour volume, as the growth difference between control and LDHAlow tumours was lost in Ifng−/− mice. To establish the mechanism by which tumour-derived lactic acid could perturb cytokine production of tumour-infiltrating T and NK cells, the authors incubated CD8+ T cells in the presence of 13C1-labelled lactate and hydrochloric acid (HCl) to replicate conditions of high lactic acid in the tumour microenvironment. This experiment revealed that lactic acid uptake was sufficient to cause intracellular acidification and suppress expression of nuclear factor of activated T cells (NFAT), a regulator of IFNG gene expression during T and NK cell activation.
Finally, the authors related their mouse findings to human melanoma data by analysing a cohort of 44 patients with metastatic melanoma and showed that LDHA expression negatively correlated with survival. Furthermore, biopsy samples from cutaneous melanoma metastases were found to have higher lactate levels with fewer activated T cells than those of normal skin. In summary, this work highlights how LDHA-mediated lactic acid can be used by a tumour as an immunosuppressive metabolite to induce immune tolerance and promote tumour growth.
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. https://dx.doi.org/10.1016/j.cmet.2016.08.011 (2016)
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Dart, A. Lactic acid: not just a waste product?. Nat Rev Cancer 16, 677 (2016). https://doi.org/10.1038/nrc.2016.109