EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells

Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of a...

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Autores principales:	Christopher J. Stairiker, Sophia Xiao Pfister, Eleanore Hendrickson, Wenjing Yang, Tao Xie, Catherine Lee, Haikuo Zhang, Christopher Dillon, Graham D. Thomas, Shahram Salek-Ardakani
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	EZH2 CD8 T cell Bim CD137 (4-1BB) Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/b009c34667ac4334bd59e24939d35690
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spelling	oai:doaj.org-article:b009c34667ac4334bd59e24939d356902021-12-03T11:20:13ZEZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells1664-322410.3389/fimmu.2021.770080https://doaj.org/article/b009c34667ac4334bd59e24939d356902021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.770080/fullhttps://doaj.org/toc/1664-3224Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB). Our data show that EZH2i compromise the efficacy of α4-1BB in both CT26 colon carcinoma and in an in vivo protein immunization model. We link this to reduced effector survival and increased BIM expression in CD8+ T cells upon EZH2i treatment. These data support the requirement of EZH2 function in 4-1BB-mediated CD8+ T cell expansion and effector programming and emphasize the consideration that must be given when combining such antitumoral therapies.Christopher J. StairikerSophia Xiao PfisterEleanore HendricksonWenjing YangTao XieCatherine LeeHaikuo ZhangChristopher DillonGraham D. ThomasShahram Salek-ArdakaniFrontiers Media S.A.articleEZH2CD8T cellBimCD137 (4-1BB)Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	EZH2 CD8 T cell Bim CD137 (4-1BB) Immunologic diseases. Allergy RC581-607
spellingShingle	EZH2 CD8 T cell Bim CD137 (4-1BB) Immunologic diseases. Allergy RC581-607 Christopher J. Stairiker Sophia Xiao Pfister Eleanore Hendrickson Wenjing Yang Tao Xie Catherine Lee Haikuo Zhang Christopher Dillon Graham D. Thomas Shahram Salek-Ardakani EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
description	Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB). Our data show that EZH2i compromise the efficacy of α4-1BB in both CT26 colon carcinoma and in an in vivo protein immunization model. We link this to reduced effector survival and increased BIM expression in CD8+ T cells upon EZH2i treatment. These data support the requirement of EZH2 function in 4-1BB-mediated CD8+ T cell expansion and effector programming and emphasize the consideration that must be given when combining such antitumoral therapies.
format	article
author	Christopher J. Stairiker Sophia Xiao Pfister Eleanore Hendrickson Wenjing Yang Tao Xie Catherine Lee Haikuo Zhang Christopher Dillon Graham D. Thomas Shahram Salek-Ardakani
author_facet	Christopher J. Stairiker Sophia Xiao Pfister Eleanore Hendrickson Wenjing Yang Tao Xie Catherine Lee Haikuo Zhang Christopher Dillon Graham D. Thomas Shahram Salek-Ardakani
author_sort	Christopher J. Stairiker
title	EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
title_short	EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
title_full	EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
title_fullStr	EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
title_full_unstemmed	EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells
title_sort	ezh2 inhibition compromises α4-1bb-mediated antitumor efficacy by reducing the survival and effector programming of cd8+ t cells
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b009c34667ac4334bd59e24939d35690
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EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells

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