AUTHOR=Stairiker Christopher J. , Pfister Sophia Xiao , Hendrickson Eleanore , Yang Wenjing , Xie Tao , Lee Catherine , Zhang Haikuo , Dillon Christopher , Thomas Graham D. , Salek-Ardakani Shahram TITLE=EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.770080 DOI=10.3389/fimmu.2021.770080 ISSN=1664-3224 ABSTRACT=

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.