Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer.

Renhong Huang, Han Wang, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen, Zheng Wang

Frontiers in immunology 2023

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Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC. In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification. We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression. Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC. Copyright © 2023 Huang, Wang, Hong, Wu, Huang, He, Chen, Li, Chen, Shen and Wang.

Citation

Renhong Huang, Han Wang, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen, Zheng Wang. Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer. Frontiers in immunology. 2023;14:1251643