GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model

Cancer Immunology Research
Simran S SabharwalLuis A Zúñiga

Abstract

GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8+ T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8+ T-cell metabolism. We found activated, GITR-treated CD8+ T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) in vitro Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an in vitro model of PD-L1-induced CD8+ T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti-PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymp...Continue Reading

References

Jun 23, 1997·FEBS Letters·N Pullen, G Thomas
Jul 18, 2002·Immunity·Kenneth A FrauwirthCraig B Thompson
Mar 3, 2004·European Journal of Immunology·Simona RonchettiCarlo Riccardi
Feb 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Julia HauerHartmut Engelmann
May 20, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Teresa Ramirez-MontagutMarcel R M van den Brink
Nov 21, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Pengfei ZhouXiao Min Schebye
May 19, 2010·Cancer Immunology, Immunotherapy : CII·David CoeJian-Guo Chai
Nov 16, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Laura M SnellTania H Watts
May 3, 2011·Trends in Biochemical Sciences·Michelle C MendozaJohn Blenis
Oct 24, 2012·Cancer Research·Michael PlattenBenoît J Van den Eynde
Jan 22, 2013·Nature Reviews. Drug Discovery·Michael CroftCarl F Ware
Sep 6, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Magali GrangeNathalie Auphan-Anezin
Mar 17, 2015·Trends in Immunology·Peter J Siska, Jeffrey C Rathmell
Mar 20, 2015·Science Translational Medicine·Siwen Hu-LieskovanAntoni Ribas
Jul 3, 2015·Oncoimmunology·Li X ZhuSherven Sharma
Jul 15, 2015·Frontiers in Immunology·Silvia A Fuertes MarracoDaniel E Speiser
Oct 2, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Young H KimByoung S Kwon
Dec 10, 2015·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Sandrine AspeslaghAurélien Marabelle
Jan 12, 2016·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Amani MakkoukHolbrook E Kohrt
Jan 26, 2016·Immunotherapy·David AllardJohn Stagg
Mar 15, 2016·Cellular & Molecular Immunology·Beom K ChoiByoung S Kwon
Sep 4, 2016·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Deborah A KneeJennifer L Brogdon
Nov 15, 2016·The International Journal of Biochemistry & Cell Biology·Hugh Ip, Tariq Sethi
Nov 20, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Adil I DaudOmid Hamid
Nov 25, 2016·Future Oncology·Paul LetendreYousef Zakharia
Dec 13, 2016·Cancer Immunology Research·Nicole E ScharpingGreg M Delgoffe
Feb 28, 2017·Journal for Immunotherapy of Cancer·Patrick A OttJedd D Wolchok
Sep 19, 2017·Cell·Ramon I Klein GeltinkErika L Pearce

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Citations

Aug 16, 2019·Physiological Reviews·Carla Riera-DomingoMassimiliano Mazzone
Nov 6, 2018·Science Immunology·André Veillette, Dominique Davidson
Sep 25, 2019·International Journal of Molecular Sciences·Chloé LaplagneMary Poupot
Jul 8, 2020·Nature Reviews. Cancer·Robert D Leone, Jonathan D Powell
Mar 12, 2020·Immune Network·Seongju Jeong, Su-Hyung Park
Mar 14, 2019·Immunology·Mariela A Moreno AyalaMichel DuPage
Mar 28, 2019·Nature Reviews. Clinical Oncology·Xiaoyun LiPing-Chih Ho
Aug 21, 2020·ESMO Open·Giulia BuzzattiLucia Del Mastro
Oct 3, 2019·Cancer Immunology Research·Alvaro TeijeiraGreg M Delgoffe
Mar 16, 2021·Frontiers in Immunology·Yun-Shiuan Olivia HsuChun-Bing Chen
Apr 16, 2021·Science Translational Medicine·Junichi MurakamiMarc de Perrot
Jul 10, 2021·Cellular & Molecular Immunology·Bradley I ReinfeldJeffrey C Rathmell
Aug 7, 2021·Biomedicines·Ezequiel MonferrerTomás Álvaro Naranjo
Aug 31, 2021·International Journal of Cancer. Journal International Du Cancer·Yiming LiZhinan Chen

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