Summary of project PR001308

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench,, where it has been assigned Project ID PR001308. The data can be accessed directly via it's Project DOI: 10.21228/M8N98X This work is supported by NIH grant, U2C- DK119886.


Project ID: PR001308
Project DOI:doi: 10.21228/M8N98X
Project Title:Glutaminase inhibition impairs CD8 T cell activation in STK11/Lkb1 deficient lung cancer
Project Type:untargeted LCMS metabolomics of GM mice lung tumors upon treatment
Project Summary:The tumor microenvironment (TME) contains a rich source of nutrients that sustain cell growth and ultimately facilitate tumor progression. The availability of glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert anti-tumor function. Recently, inhibition of glutaminase, the enzyme that hydrolyzes glutamine to glutamate, has garnered interest as an approach to both decrease tumor metabolism and growth, while increasing available glutamine in the TME for effector T cells. Checkpoint blockade immunotherapy unleashes anti-tumor effector capabilities of T cells, and although there are good responses in many solid tumors, a significant proportion of patients respond poorly. In lung adenocarcinoma, response to immunotherapy is reported to be impaired in KRAS-mutant patients harboring concurrent KEAP1 and STK11/Lkb1 mutations. To investigate the metabolism and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated a series of murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape seen in patients. Here we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1 checkpoint immunotherapy. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and cytotoxic activation of tumor-infiltrating CD8 T cells. Thus, CD8 T cells exposed to checkpoint immunotherapy have a dependence on glutamine and reliance on glutaminase activity and are negatively impacted by the glutaminase inhibitor in this highly activated state. Therefore, we discern that the combination of immunotherapy and glutaminase inhibition is not efficacious for CD8 T cell activation in the tumor microenvironment.
Institute:The Walter and Eliza Hall Institute of Medical Research
Laboratory:Kate Sutherland
Last Name:Best
First Name:Sarah
Address:1G, Royal Parade, Parkville VIC 3052
Publications:Glutaminase inhibition impairs CD8 T cell activation in STK11/Lkb1 deficient lung cancer
Contributors:Sarah A. Best, Patrick M. Gubser, Shalini Sethumadhavan, Ariena Kersbergen, Yashira L. Negrón Abril, Joshua Goldford, Katherine Sellers, Waruni Abeysekera, Alexandra L. Garnham, Jackson A. McDonald, Clare E. Weeden, Dovile Anderson, David Pirman, Thomas P. Roddy, Darren J. Creek, Axel Kallies, Gillian Kingsbury and Kate D. Sutherland

Summary of all studies in project PR001308

Study IDStudy TitleSpeciesInstituteAnalysis
(* : Contains Untargted data)
(* : Contains raw data)
ST002066 Glutaminase inhibition impairs CD8 T cell activation in STK11/Lkb1 deficient lung cancer Mus musculus The Walter and Eliza Hall Institute of Medical Research MS 2022-05-02 1 31 Uploaded data (3.1G)*