Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer
- Author(s)
- Best, SA; Gubser, PM; Sethumadhavan, S; Kersbergen, A; Negrón Abril, YL; Goldford, J; Sellers, K; Abeysekera, W; Garnham, AL; McDonald, JA; Weeden, CE; Anderson, D; Pirman, D; Roddy, TP; Creek, DJ; Kallies, A; Kingsbury, G; Sutherland, KD;
- Details
- Publication Year 2022-04-23,Volume 34,Issue #6,Page 874-887 e6
- Journal Title
- Cell Metabolism
- Abstract
- 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.
- Publisher
- Cell Press
- Keywords
- Keap1; Kras; STK11/Lkb1; glutaminase; glutamine; immune microenvironment; immunotherapy; lung adenocarcinoma; metabolism
- Research Division(s)
- Bioinformatics; Cancer Biology And Stem Cells
- PubMed ID
- 35504291
- Publisher's Version
- https://doi.org/10.1016/j.cmet.2022.04.003
- Open Access at Publisher's Site
https://doi.org/10.1016/j.cmet.2022.04.003- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-05-11 10:40:09
Last Modified: 2022-06-16 10:59:16