Unbalanced Glutamine Partitioning Between CD8T Cells And Cancer Cells Accompanied By Tumor Immunity Dysfunction In Hepatocellular Carcinoma

Aim: The glutamine metabolism is both critical for the proliferation of cancer cells and activation of CD8 T cells to kill cancer cells.We aimed to explore the relationship of cancer cell glutamine metabolism and the immunophenotype of CD8 T cells and defined a quantitative tool to evaluate the differences of glutamine metabolism between cancer cells and immune cells.Methods: We calculated the cancer cell glutamine-metabolism-related gene expression scores in the TCGA cohort and divided the patients into high score group and low score group base on glutamine metabolism-related genes.At the same time,we showed the prognostic differences between the two groups.The prognostic value of cancer cell glutamine metabolism was determined by the Cox proportional hazards model.Further,we performed quantitative assessment of glutamine metabolism activity in tumor cells and CD8 T cells in the singlecell RNA sequencing data and illustrated the metabolic reprogramming and immune remodeling of CD8 T cells under the pressure of cancer cell glutamine metabolism.Next,the effect of glutamine metabolism inhibitor on the efficacy of PD-1 blocker was explored in animal experiments.Results: In a TCGA cohort,we found that patients with high scores of glutamine-metabolism-related genes showed poor prognoses,and that a high score of glutamine-metabolism-related genes was an independent risk factor for HCC patients.Next,we defined two specific types of CD8 effector T cells in the single-cell RNA sequencing cohort,namely immunosuppressive CD8-TefAPOC2 and tumor-killing CD8-Tef-GZMA.We found that,in some patients,the glutamine metabolism gene scores of tumor cells were significantly higher than those of CD8 T cells,while decreased ratios of CD8-Tef-GZMA and suppressed tumor-killing activity of CD8-Tef-APOC2 were observed.A further genetic dynamics pseudotime analysis suggested that immune remodeling of these two subpopulations was accompanied by metabolic reprogramming.CD8-Tef-APOC2 in the dominant group tended to metabolize exogenous lipids,while the metabolic program of CD8-Tef-GZMA in the nondominant group was characterized by amino acid and endogenous lipid synthesis.In addition,we found that the glutamine metabolism inhibitor JHU083 facilitated CD8 T cells infiltration and improved the efficacy of PD-1 blockers.Conclusions: We proposed a new tool to quantify the glutamine partitioning between tumor cells and CD8 T cells,through which the unique immune microenvironment could be identified at the transcriptome level.Furthermore,the simultaneous destruction of the glutamine metabolism in tumor cells and CD8 T cells facilitated the enrichment of tumor-infiltrating CD8 T cells and enhanced the efficacy of immunotherapy.