Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun 7;34(6):874-887.e6.
doi: 10.1016/j.cmet.2022.04.003. Epub 2022 May 2.

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

Sarah A Best  1 , Patrick M Gubser  2 , Shalini Sethumadhavan  3 , Ariena Kersbergen  4 , Yashira L Negrón Abril  3 , Joshua Goldford  3 , Katherine Sellers  3 , Waruni Abeysekera  5 , Alexandra L Garnham  5 , Jackson A McDonald  6 , Clare E Weeden  7 , Dovile Anderson  8 , David Pirman  3 , Thomas P Roddy  3 , Darren J Creek  8 , Axel Kallies  2 , Gillian Kingsbury  3 , Kate D Sutherland  9
Affiliations
Free article

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

Sarah A Best et al. Cell Metab. .
Free article

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.

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

PubMed Disclaimer

Conflict of interest statement

Declaration of interests This work was partially funded by a sponsored research agreement with Agios Pharmaceuticals. At the time the research was conducted, T. Roddy was employed by Agios Pharmaceuticals and had employee-related financial interests there. At the time of manuscript submission, T. Roddy was employed by Atavistik Bio and has no financial interests related to the work herein. D. Pirman is an employee and stockholder of Agios Pharmaceuticals and J. Goldford is a consultant for Agios Pharmaceutical and Atavistik Bio. K. Sutherland has received an Honorarium from Cygnal Therapeutics and direct research support from Pfizer Pharmaceuticals outside of the submitted work.

Publication types

MeSH terms

Substances