EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function Journal Article
| Authors: | Isshiki, Y.; Chen, X.; Teater, M.; Karagiannidis, I.; Nam, H.; Cai, W.; Meydan, C.; Xia, M.; Shen, H.; Gutierrez, J.; Easwar Kumar, V.; Carrasco, S. E.; Ouseph, M. M.; Yamshon, S.; Martin, P.; Griess, O.; Shema, E.; Porazzi, P.; Ruella, M.; Brentjens, R. J.; Inghirami, G.; Zappasodi, R.; Chadburn, A.; Melnick, A. M.; Béguelin, W. |
| Article Title: | EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function |
| 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. © 2024 Elsevier Inc. |
| Keywords: | controlled study; human cell; genetics; nonhuman; cd8 antigen; t lymphocyte; t-lymphocytes; mouse; phenotype; animal; animals; mice; animal tissue; cell function; cancer immunotherapy; animal experiment; animal model; cell line, tumor; b cell lymphoma; regulatory t lymphocyte; immunology; immunotherapy; t-lymphocytes, regulatory; tumor burden; epigenetics; immunogenicity; tumor cell line; lymphoma; chimeric antigen receptor; lymphoma, large b-cell, diffuse; follicular lymphoma; lymphoma, follicular; therapy; adoptive immunotherapy; immunotherapy, adoptive; dlbcl; tumor microenvironment; transcription factor ezh2; ezh2; procedures; diffuse large b cell lymphoma; ezh2 protein, human; bispecific antibody; enhancer of zeste homolog 2 protein; cellular immunotherapy; humans; human; article; bispecific antibodies; car-t; receptors, chimeric antigen; t cell immunotherapy |
| Journal Title: | Cancer Cell |
| Volume: | 43 |
| Issue: | 1 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2025-01-13 |
| Start Page: | 49 |
| End Page: | 68.e9 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2024.11.006 |
| PUBMED: | 39642889 |
| PROVIDER: | scopus |
| PMCID: | PMC11732734 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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