@article{72217f74a5aa4e4b950522df1429dc37,
title = "Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer",
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 = "glutaminase, glutamine, immune microenvironment, immunotherapy, KEAP1, KRAS, lung adenocarcinoma, metabolism, STK11/Lkb1",
author = "Best, {Sarah A.} and Gubser, {Patrick M.} and Shalini Sethumadhavan and Ariena Kersbergen and {Negr{\'o}n Abril}, {Yashira L.} and Joshua Goldford and Katherine Sellers and Waruni Abeysekera and Garnham, {Alexandra L.} and McDonald, {Jackson A.} and Weeden, {Clare E.} and Dovile Anderson and David Pirman and Roddy, {Thomas P.} and Creek, {Darren J.} and Axel Kallies and Gillian Kingsbury and Sutherland, {Kate D.}",
note = "Funding Information: We are grateful to S. Oliver, L. Johnson, K. Hughes, and R. Monaghan for animal husbandry; L. Scott for genotyping; and S. Monard in the WEHI Flow Cytometry Facility and E. Tsui in the WEHI Histology Facility for expert support. Schematics were generated by P. Maltezos (WEHI) and using https://biorender.com/. Untargeted metabolomics analysis was performed at the Monash Proteomics and Metabolomics Facility. We are thankful to A.M. Paterson (Agios Pharmaceuticals) and D.H. Gray (WEHI) for critical reading of the manuscript and useful discussions. This work was partially funded by a sponsored research agreement with Agios Pharmaceuticals and supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant to K.D.S. (GNT1138275) and S.A.B. (GNT1159002) and a Priority-Driven Collaborative Cancer Research Scheme Grant funded by Cancer Australia to S.A.B. (2003127). K.D.S. is supported by a Victorian Cancer Agency Mid-Career Research Fellowship (18003) and the Peter and Julie Alston Centenary Fellowship. P.M.G. is supported by the Swiss National Foundation (P300PB_177934) and the Novartis Foundation for Medical-Biological Research, and J.A.M. is supported by a University of Melbourne Research Scholarship. This work was made possible through the Victorian Government Operational Infrastructure Support and Australian Government. The experiments were conceived and designed by S.A.B. S.S. T.P.R. A.K. G.K. and K.D.S. Experiments were performed by S.A.B. with the assistance of A.K. P.M.G. S.S. J.A.M. and C.E.W. Bioinformatics analysis of RNA-seq was performed by W.A. and A.L.G. Metabolomics was performed by D.A. D.J.C. K.S. Y.L.N.A. J.G. and D.P. The manuscript was written by S.A.B. and K.D.S. 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. Funding Information: We are grateful to S. Oliver, L. Johnson, K. Hughes, and R. Monaghan for animal husbandry; L. Scott for genotyping; and S. Monard in the WEHI Flow Cytometry Facility and E. Tsui in the WEHI Histology Facility for expert support. Schematics were generated by P. Maltezos (WEHI) and using https://biorender.com/ . Untargeted metabolomics analysis was performed at the Monash Proteomics and Metabolomics Facility. We are thankful to A.M. Paterson (Agios Pharmaceuticals) and D.H. Gray (WEHI) for critical reading of the manuscript and useful discussions. This work was partially funded by a sponsored research agreement with Agios Pharmaceuticals and supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant to K.D.S. ( GNT1138275 ) and S.A.B. ( GNT1159002 ) and a Priority-Driven Collaborative Cancer Research Scheme Grant funded by Cancer Australia to S.A.B. (2003127). K.D.S. is supported by a Victorian Cancer Agency Mid-Career Research Fellowship ( 18003 ) and the Peter and Julie Alston Centenary Fellowship. P.M.G. is supported by the Swiss National Foundation ( P300PB_177934 ) and the Novartis Foundation for Medical-Biological Research , and J.A.M. is supported by a University of Melbourne Research Scholarship. This work was made possible through the Victorian Government Operational Infrastructure Support and Australian Government . Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jun,
day = "7",
doi = "10.1016/j.cmet.2022.04.003",
language = "English",
volume = "34",
pages = "874--887.e6",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Elsevier",
number = "6",
}
