Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response.

Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8+ T cell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8+ T cells and enhanced anti-tumor immunity. CD8+ T cells from PP2Cm-/- mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake, as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ T cell hyper-functions and synergizes with anti-PD-1, in line with a better prognosis in NSCLC patients containing high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ T cells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.

DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically.

Gastric cancer (GC) is among the most malignant cancers with high incidence and poor prognoses worldwide as well as in China. dCTP pyrophosphatase 1 (DCTPP1) is overexpressed in GC with a poor prognosis. Given chemotherapeutic drugs share similar structures with pyrimidine nucleotides, the role of DCTPP1 in affecting the drug sensitivity in GC remains unclear and is worthy of investigation. In the present study, we reported that DCTPP1-knockdown GC cell line BGC-823 exhibited more sensitivity to 5-fluorouracil (5-FU), demonstrated by the retardation of cell proliferation, the increase in cell apoptosis, cell cycle arrest at S phase and more DNA damages. Multidrug resistance 1 (MDR1) expression was unexpectedly down-regulated in DCTPP1-knockdown BGC-823 cells together with more intracellular 5-FU accumulation. This was in large achieved by the elevated methylation in promoter region of MDR1 gene. The intracellular 5-methyl-dCTP level increased in DCTPP1-knockdown BGC-823 cells as well. More significantly, the strong correlation of DCTPP1 and MDR1 expression was detectable in clinical GC samples. Our results thus imply a novel mechanism of chemoresistance mediated by the overexpression of DCTPP1 in GC. It is achieved partially through decreasing the concentration of intracellular 5-methyl-dCTP, which in turn results in promoter hypomethylation and hyper-expression of drug resistant gene MDR1. Our study suggests DCTPP1 as a potential indicative biomarker for the predication of chemoresistance in GC.