New strategy for tumor immunotherapy!Deciphering lactic acid metabolism in Treg cells

2022-04-25 0 By

Writing | ice latte coordinating editor | yi antibacterial “metabolic imbalances” has long been considered to be one of the symbols of # # tumor.Specifically, cancer cells use glucose to promote aerobic glycolysis to survive (known as the “Warburg effect”).In such a low glucose, high lactate microenvironment, T cells are difficult to perform normal functions.For Treg cells, specific metabolic reprogramming occurs in the tumor microenvironment.However, many key scientific questions remain unanswered: How do metabolites in the tumor microenvironment directly affect Treg cells?Do Treg cells have specific metabolic checkpoints in response to specific metabolic microenvironments?The above problems still need systematic exploration.27 January 2022,Professor Hiroyoshi Nishikawa’s team published online titled TITLED LACTObacillus promotes PD-1 expression in Regulatory T cells in Cancer CellA highly glycolytic tumor microenvironment study found that lactic acid can induce THE expression of PD-1 in Treg cells in the highly glycolytic tumor microenvironment, and found that MCT1 is an important metabolic checkpoint in this process.It provides new clues for understanding the metabolic and immune “balance” of tumor microenvironment.To explore the association between tumor metabolic characteristics and Effector Treg cells (eTreg cells), we used RNA-SEQ and flow cytometry to study gastric cancer and non-small cell lung cancer samples.It was found that tumor tissues with high infiltration of eTreg showed characteristics of high glycolysis metabolism and MYC activation.We further found that tumor tissues with high glycolysis /MYC expression showed high infiltration of PD-1+eTreg cells, while PD-1+CD8+T cells showed low infiltration, suggesting that tumor metabolites may play a specific role in the functioning of eTreg cells.Since lactic acid is the end product of tumor glycolysis, we found that lactate transporter MCT1 (Slc16a1) was specifically enriched in PD-1+eTreg, but not in CD8+T cells.Chip-seq demonstrated that FOXP3, a transcription factor specific for Treg cells, could directly bind to MCT1 DNA.These results all suggest that lactic acid may play an important role in the function and phenotype of Treg cells.Therefore, the researchers explored the association between lactic acid metabolism and PD-1 expression in eTreg cells.Lactate gradient stimulation showed that pD-1 expression of eTreg cells increased significantly with the increase of lactate concentration, while CD8+T cells showed an opposite trend.Mechanically, we suggest that lactic acid uptake from the microenvironment by Treg cells via MCT1 may be metabolized into Phosphoenol pyruvate (PEP) in Treg cells, which is the immune metabolic checkpoint of T cells.Therefore, we explored the association between lactic acid concentration and phosphoenolpyruvate, and found that lactic acid promoted the increase of eTreg phosphoenolpyruvate, but not in CD8+T cells.We further explored the relationship between MCT1 inhibitors and T cell phenotype, and found that pD-1 expression of eTreg cells decreased significantly in a concentration-dependent manner under high lactate conditions, and MCT1 inhibitors reduced eTreg proliferation and enhanced eTreg apoptosis.These results suggest that eTreg cells are more inhibitory under high lactate concentration.In MCT1 deficient mice (Slc16a1 +/- mice), PD-1 expression in Treg cells was significantly reduced.These results suggest that high lactate environment can enable eTreg cells to use MCT1 to absorb lactic acid and regulate PD-1, thus affecting the function and phenotype of eTreg cells.Figure 1. Lactic acid gradient stimulation experiment: The expression of PD-1 in effector Treg cells increased significantly with the increase of lactic acid concentration, while CD8+T cells showed an opposite trend. Finally, the author systematically explored the scientific issue of “cross interaction between tumor and Treg cells”.First, we found that overexpression of MYC produced higher levels of lactic acid in vitro and in vivo and increased PD-1 expression in Treg cells.However, MYC overexpression of LDHA, a key enzyme in hypoglycemic metabolism, significantly reduced lactic acid production and reversed the Treg inhibitory phenotype, and these results were consistent in THE Mc-38 colorectal cancer model, B16 melanoma model and liver metastasis model.Further inhibition of MCT1 in vivo can reduce the proportion of Treg cells in the microenvironment, inhibit THE expression of PD-1 in Treg cells, and enhance the efficacy of anti-PD-1 mab.Importantly, MYC and LDHA, a key enzyme of glucose metabolism, can predict immunotherapy efficacy in patients with gastric cancer, non-small cell lung cancer, and melanoma in independent clinical coenies, closely related to patient clinical outcome.In conclusion, this work found that tumors with high glycolysis can release excess lactic acid, thus promoting the uptake of lactic acid by Treg cells through MCT1 to enhance PD-1 expression and reshape the function and phenotype of Treg cells, which may be one of the reasons leading to drug resistance of αPD-1 immunotherapy.This study provides new clues for the design of novel immunotherapy strategies: targeting Treg cell-specific immune metabolic checkpoints may serve as a potential therapeutic strategy.Figure 2. The main findings of this study were that tumors with high glycolysis could release excessive lactic acid, thus promoting the uptake of lactic acid by Treg cells through MCT1 to enhance THE expression of PD-1 and reshape the function and phenotype of Treg cells.https://doi.org/10.1016/j.ccell.2022.01.001 in reference [1] Hanahan d. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12 (1) : 31-46. Doi: 10.1158/2159-8290. The CD – 21-1059 [2] Ho PC,Kaech SM. Reenergizing T cell anti-tumor immunity by harnessing immunometabolic checkpoints and machineries. Curr Opin Immunol. 2017;46:38-44. Doi: 10.1016 / j.c. oi 2017.04.003 [3] Angelin A, Gil – DE – Gomez L, Dahiya S,et al. Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab. 2017;25 (6) : 1282-1293. The e7. Doi: 10.1016 / j.carol carroll met 2016.12.018 [4] Zappasodi R, Serganova I, Cohen IJ,et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature. 2021;591(7851): 652-658.doi :10.1038/ S41586-021-03326-4 [5] Ho PC, Bihuniak JD, Macintyre AN,et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162 (6) : 1217-1228. The doi: 10.1016 / j.carol carroll ell. 2015.08.012