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

TitleEZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.
Publication TypeJournal Article
Year of Publication2025
AuthorsIsshiki Y, Chen X, Teater M, Karagiannidis I, Nam H, Cai W, Meydan C, Xia M, Shen H, Gutierrez J, Kumar VEaswar, Carrasco SE, Ouseph MM, Yamshon S, Martin P, Griess O, Shema E, Porazzi P, Ruella M, Brentjens RJ, Inghirami G, Zappasodi R, Chadburn A, Melnick AM, Béguelin W
JournalCancer Cell
Volume43
Issue1
Pagination49-68.e9
Date Published2025 Jan 13
ISSN1878-3686
KeywordsAnimals, Cell Line, Tumor, Clinical Trials as Topic, Enhancer of Zeste Homolog 2 Protein, Humans, Immunotherapy, Immunotherapy, Adoptive, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Mice, Receptors, Chimeric Antigen, T-Lymphocytes, Tumor Microenvironment
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.

DOI10.1016/j.ccell.2024.11.006
Alternate JournalCancer Cell
PubMed ID39642889
PubMed Central IDPMC11732734
Grant ListP01 CA214278 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
R01 CA270245 / CA / NCI NIH HHS / United States
R21 CA277513 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R37 CA262362 / CA / NCI NIH HHS / United States