How does a low-glucose, high-lactate environment in tumors affect T cell function?

"Metabolic imbalance" has long been regarded as one of the hallmarks of tumors [

Specifically, cancer cells can utilize glucose to promote aerobic glycolysis for survival (known as the "Warburg effect") [

In such a low-sugar, high-lactate microenvironment, it is difficult for T cells to function normally [

Treg cells undergo specific metabolic reprogramming in the tumor microenvironment [3-

But many key scientific questions remain unanswered: How do metabolites in the tumor microenvironment act directly on Treg cells?

Do Treg cells have specific metabolic checkpoints to respond to specific metabolic microenvironments? The above questions still need to be systematically explor.

The research group of Pr.

Treg cells were induced to express PD-1 in MCTs, and MCT1 was found to be an important metabolic checkpoint in this process, providing new clues to gain insight into the metabolic and immune "balance" of the tumor microenvironme.

To explore the relationship between tumor metabolic signatures and effector Treg cells (eTreg cells), the researchers used RNA-seq and flow cytometry in gastric cancer and non-small cell lung cancer samples and found that eTreg were highly infiltrated Tumor tissues exhibit features of high glycolytic metabolism and MYC activati.

The authors further found that in tumor tissues with high glycolysis/high expression of MYC, the infiltration of PD-1+ eTreg cells was high, but the infiltration of PD-1+ CD8+ T cells was low, suggesting that tumor metabolites may affect eTreg cel.

Given that lactate is the end product of tumor glycolysis, the authors found that the lactate transporter MCT1 (Slc16a1) was specifically enriched in PD-1+ eTreg but not CD8+ T cel.

ChIP-seq revealed that Treg cell-specific transcription factor FOXP3 can directly bind to the DNA of MCT

These results suggest that lactate may play an important role in the function and phenotype of Treg cel.

Therefore, we explored the relationship between lactate metabolism and PD-1 expression in eTreg cel.

Mechanistically, the authors suggest that when Treg cells take up lactate from the microenvironment via MCT1, lactate may be metabolized to phosphoenolpyruvate (PEP) in Treg cells, which are T cel.

Therefore, we explored the correlation of lactate concentration with phosphoenolpyruvate and found that lactate increased eTreg phosphoenolpyruvate, but not in CD8+ T cel.

The authors further used MCT1 inhibitor to explore its relationship with T cell phenotype, and found that under high lactate conditions, the expression of PD-1 in eTreg cells was significantly reduced in a concentration-dependent manner, and MCT1 inhibitor could reduce eTreg proliferation, Enhanced eTreg apoptos.

These results suggest that eTreg cells have a stronger inhibitory effect at high lactate concentratio.

These results suggest that a high lactate environment enables eTreg cells to utilize MCT1 to uptake lactate to upregulate PD-1, thereby affecting eTreg cell function and phenoty.

Finally, the scientific question of "tumor-Treg cell interaction" is systematically explor.

First, the authors found that overexpression of MYC produced higher levels of lactate and increased PD-1 expression in Treg cells in vitro and in vivo; while in myc overexpressed cells, knockout of LDHA, a key enzyme in glucose metabolism, significantly reduced lactate leve.

generation, reversed the phenotypic suppression of Treg cells, and these results were more consistent in the MC-38 intestinal cancer model, the B16 melanoma model, and the liver metastasis mod.

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 monoclonal antibodi.

Importantly, MYC and LDHA are key enzymes in glucose metabolism that predict immunotherapy outcomes in patients with gastric cancer, non-small cell lung cancer, and melanoma in independent clinical cohorts, and are closely related to patient clinical outcom.

In conclusion, the present study found that hyperglycolytic tumors can release excess lactate, thereby promoting lactate uptake by Treg cells through MCT1, enhancing PD-1 expression, and remodeling Treg cell function and phenotype, which may lead to αPD- One of the reasons for immunotherapy resistan.

This study provides new clues for designing new immunotherapy strategies: targeting Treg cell-specific immune metabolic checkpoints may become a potential therapeutic strate.

This study mainly found that hyperglycolytic tumors can release excess lactate, thereby promoting lactate uptake by Treg cells through MCT1, enhancing PD-1 expression, and remodeling Treg cell function and phenoty.

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