Suppressing glutamine metabolism in the pancreatic cancer microenvironment can enhance the anti-tumor effect of CD8 T cells and promote the efficacy of immunotherapy.

OBJECTIVE

This study aims to investigate the relationship between tumor cell glutamine metabolism and CD8 T cells, with the goal of providing new insights to improve immunotherapy for pancreatic cancer.

METHODS

Using the The Cancer Genome Atlas - Pancreatic Adenocarcinoma (TCGA-PAAD) cohort, we computed gene expression scores related to glutamine metabolism and stratified patients into high- and low-score groups. Prognosis and differences in immune cell anti-tumor activity were compared between these groups. We further utilized single-cell RNA sequencing data to quantitatively assess the expression of glutamine metabolism-related pathways in tumor cells. Based on tumor-specific glutamine metabolism gene expression, patients were again classified into high- and low-score groups. The immune remodeling effects exerted by tumor cell glutamine metabolism on CD8 T cells were subsequently investigated. To examine the impact of perturbing glutamine metabolism within the tumor microenvironment on CD8 T cell phenotype and the efficacy of PD-1 inhibitors, we conducted in vivo animal experiments.

RESULTS

we analyzed the pancreatic cancer dataset in the cancer gene atlas database. We found that tumor glutamine metabolism was negatively correlated with patient prognosis and anti-tumor activity. Next, we defined two types of CD8 effector T cells in single-cell RNA sequencing data, namely, effector memory T cells (CD8-Tem) and terminally differentiated effector memory T cells (CD8-Temra). Under the pressure of high glutamine metabolism in tumor cells, the cytotoxicity of the CD8-Tem subset was reduced, and its immaturity score increased, while the exhaustion score of the CD8-Temra subset increased. Pseudotime analysis showed that CD8-Tn in the low-scoring group mainly developed into CD8-Tem subset, and its immune activation pathway was significantly upregulated. In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the infiltration of CD4 and CD8 T cells and T lymphocyte differentiation, and increased the efficacy of PD-1 inhibitors. Glutamine inhibitors can inhibit the apoptosis of immune cells in the tumor microenvironment, while promoting CD8 T cells activation and cytotoxicity increase.

CONCLUSION

Inhibition of glutamine metabolism within the pancreatic cancer microenvironment results in reduced apoptosis of immune cells, heightened activation and cytotoxicity of CD8 T cells, and a substantial enhancement in the therapeutic efficacy of immunotherapy.