EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function

Yusuke Isshiki, Xi Chen, Matt Teater, Ioannis Karagiannidis, Henna Nam, Winson Cai, Cem Meydan, Min Xia, Hao Shen, Johana Gutierrez, Vigneshwari Easwar Kumar, Sebastián E. Carrasco, Madhu M. Ouseph, Samuel Yamshon, Peter Martin, Ofir Griess, Efrat Shema, Patrizia Porazzi, Marco Ruella, Renier J. BrentjensGiorgio Inghirami, Roberta Zappasodi, Amy Chadburn, Ari M. Melnick, Wendy Béguelin

Research output: Contribution to journalArticlepeer-review

Abstract

T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.

Original languageEnglish
Pages (from-to)49-68.e9
JournalCancer Cell
Volume43
Issue number1
DOIs
StatePublished Online - 5 Dec 2024

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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