Summary of Study ST002066
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, 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.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST002066 |
| Study Title | Glutaminase inhibition impairs CD8 T cell activation in STK11/Lkb1 deficient lung cancer |
| Study Type | Biomedical research |
| Study Summary | To characterize the impact of KRAS co-mutations KEAP1 and STK11/Lkb1 on the metabolic and immune microenvironment of lung adenocarcinoma in immune-intact models, we generated a cohort of genetically engineered mouse models (GEMMs) to reflect the diverse tumor suppressor landscape seen in patients. Mice carrying the KrasG12D allele (K)21 were crossed with Keap1flox/flox (KK)22 and/or Lkb1flox/flox (KKL, KL)23 mice and genetic recombination induced by intranasal inhalation of Ad5-CMV-Cre adenovirus. We interrogated the metabolites present in lung tumor nodules collected from cohorts of KK, KL and KKL mice. |
| Institute | The Walter and Eliza Hall Institute of Medical Research |
| Laboratory | Kate Sutherland |
| Last Name | Sarah |
| First Name | Best |
| Address | 1G, Royal Parade, Parkville VIC 3052, Australia |
| best@wehi.edu.au | |
| Phone | +61-3-9345-2452 |
| Submit Date | 2022-01-18 |
| Num Groups | 5 |
| Total Subjects | 25 |
| Num Males | 17 |
| Num Females | 8 |
| Study Comments | L lobe of mice lung |
| Publications | Glutaminase inhibition impairs CD8 T cell activation in STK11/Lkb1 deficient lung cancer |
| Raw Data Available | Yes |
| Raw Data File Type(s) | raw(Thermo) |
| Analysis Type Detail | LC-MS |
| Release Date | 2022-05-02 |
| Release Version | 1 |
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Project:
| 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 |
| Email: | best@wehi.edu.au |
| Phone: | +61-3-9345-2452 |
| 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 |
