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

Authors:

• Best, Sarah A.
• Gubser, Patrick M.
• Sethumadhavan, Shalini
• Kersbergen, Ariena
• Negrón Abril, Yashira L.
• Goldford, Joshua
• Sellers, Katherine
• Abeysekera, Waruni
• Garnham, Alexandra L.
• McDonald, Jackson A.
• Weeden, Clare E.
• Anderson, Dovile
• Pirman, David
• Roddy, Thomas P.
• Creek, Darren J.
• Kallies, Axel
• Kingsbury, Gillian
• Sutherland, Kate D.

Details:

Cell Metabolism, Volume 34, Issue 6, 2022-06-07

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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.