Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer

Cell Metab. 2022 Jun 7;34(6):874-887.e6. doi: 10.1016/j.cmet.2022.04.003. Epub 2022 May 2.


The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.

Keywords: KEAP1; KRAS; STK11/Lkb1; glutaminase; glutamine; immune microenvironment; immunotherapy; lung adenocarcinoma; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases* / deficiency
  • AMP-Activated Protein Kinase Kinases* / immunology
  • AMP-Activated Protein Kinase Kinases* / metabolism
  • Adenocarcinoma of Lung* / drug therapy
  • Adenocarcinoma of Lung* / immunology
  • Adenocarcinoma of Lung* / metabolism
  • Animals
  • CD8-Positive T-Lymphocytes* / immunology
  • Glutaminase* / antagonists & inhibitors
  • Glutaminase* / immunology
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / metabolism
  • Lymphocyte Activation
  • Mice
  • Mutation
  • NF-E2-Related Factor 2 / metabolism
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras) / immunology
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Tumor Microenvironment


  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • Glutaminase
  • Proto-Oncogene Proteins p21(ras)