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Selective glutamine metabolism inhibition in tumor cells improves anti-tumor T lymphocyte activity in triple-negative breast cancer.

Deanna N. Edwards,Verra M. Ngwa,Ariel L. Raybuck,Shan Wang,Y. Hwang,Laura C. Kim,Sung Hoon Cho,Yeeun Paik,Qingfei Wang,Siyuan Zhang,H. C. Manning,J. Rathmell,Rebecca S. Cook,Mark R. Boothby,Jin Chen

Published 2020 in Journal of Clinical Investigation

ABSTRACT

Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient datasets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved anti-tumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of GSH, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing anti-tumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.

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