Title | EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function. |
Publication Type | Journal Article |
Year of Publication | 2025 |
Authors | Isshiki 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 |
Journal | Cancer Cell |
Volume | 43 |
Issue | 1 |
Pagination | 49-68.e9 |
Date Published | 2025 Jan 13 |
ISSN | 1878-3686 |
Keywords | Animals, 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. |
DOI | 10.1016/j.ccell.2024.11.006 |
Alternate Journal | Cancer Cell |
PubMed ID | 39642889 |
PubMed Central ID | PMC11732734 |
Grant List | P01 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 |