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

Journal Article (Journal Article)

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 data sets, 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 antitumor 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 glutathione, 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 antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.

Full Text

Duke Authors

Cited Authors

  • Edwards, DN; Ngwa, VM; Raybuck, AL; Wang, S; Hwang, Y; Kim, LC; Cho, SH; Paik, Y; Wang, Q; Zhang, S; Manning, HC; Rathmell, JC; Cook, RS; Boothby, MR; Chen, J

Published Date

  • February 15, 2021

Published In

Volume / Issue

  • 131 / 4

PubMed ID

  • 33320840

Pubmed Central ID

  • PMC7880417

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI140100

Language

  • eng

Conference Location

  • United States