| First Author | Isshiki Y | Year | 2025 |
| Journal | Cancer Cell | Volume | 43 |
| Issue | 1 | Pages | 49-68.e9 |
| PubMed ID | 39642889 | Mgi Jnum | J:360335 |
| Mgi Id | MGI:7798667 | Doi | 10.1016/j.ccell.2024.11.006 |
| Citation | Isshiki Y, et al. (2024) EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function. Cancer Cell |
| abstractText | 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. |
