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

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

  • J Clin Invest. 2021 Feb 15;131(4):e140100. doi: 10.1172/JCI140100.
Deanna N Edwards 1,  Verra M Ngwa 2,  Ariel L Raybuck 3,  Shan Wang 1,  Yoonha Hwang 1,  Laura C Kim 2,  Sung Hoon Cho 3,  Yeeun Paik 3,  Qingfei Wang 4 5,  Siyuan Zhang 4 5,  H Charles Manning 6 7 8 9 10,  Jeffrey C Rathmell 3 10 11,  Rebecca S Cook 2 10 12,  Mark R Boothby 1 2 3 11,  Jin Chen 1 2 10 11 12 13
Affiliations

Affiliations

  • 1 Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 2 Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
  • 3 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 4 Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana, USA.
  • 5 Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana, USA.
  • 6 Department of Chemistry.
  • 7 Center for Molecular Probes.
  • 8 Vanderbilt Institute for Imaging Sciences.
  • 9 Department of Radiology and Radiological Sciences.
  • 10 Vanderbilt-Ingram Cancer Center.
  • 11 Vanderbilt Institute for Infection, Immunology and Inflammation, and.
  • 12 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 13 Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
PMID: 33320840 DOI: 10.1172/JCI140100
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 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.

Keywords

Amino acid metabolism; Breast cancer; Cancer immunotherapy; Oncology.

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