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

Frontiers in Immunology

Christopher J. Stairiker¹  Graham D. Thomas¹  Sophia Xiao Pfister¹  Shahram Salek-Ardakani¹  Tao Xie²  Wenjing Yang²  Eleanore Hendrickson³  Catherine Lee³  Haikuo Zhang³  Christopher Dillon³ 

[1] Cancer Immunology Discovery, Worldwide Research, Development Medical, Pfizer Inc., San Diego, CA, United States;Computational Biology, Worldwide Research, Development Medical, Pfizer Inc., San Diego, CA, United States;Translational Sciences, Worldwide Research, Development Medical, Pfizer Inc., San Diego, CA, United States;

关键词: EZH2;    CD8;    T cell;    Bim;    CD137 (4-1BB);   

DOI  :  10.3389/fimmu.2021.770080

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown