TY - JOUR
T1 - EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function
AU - Isshiki, Yusuke
AU - Chen, Xi
AU - Teater, Matt
AU - Karagiannidis, Ioannis
AU - Nam, Henna
AU - Cai, Winson
AU - Meydan, Cem
AU - Xia, Min
AU - Shen, Hao
AU - Gutierrez, Johana
AU - Easwar Kumar, Vigneshwari
AU - Carrasco, Sebastián E.
AU - Ouseph, Madhu M.
AU - Yamshon, Samuel
AU - Martin, Peter
AU - Griess, Ofir
AU - Shema, Efrat
AU - Porazzi, Patrizia
AU - Ruella, Marco
AU - Brentjens, Renier J.
AU - Inghirami, Giorgio
AU - Zappasodi, Roberta
AU - Chadburn, Amy
AU - Melnick, Ari M.
AU - Béguelin, Wendy
N1 - Publisher Copyright: © 2024 Elsevier Inc.
PY - 2024/12/5
Y1 - 2024/12/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85213495863&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ccell.2024.11.006
DO - https://doi.org/10.1016/j.ccell.2024.11.006
M3 - مقالة
C2 - 39642889
SN - 1535-6108
VL - 43
SP - 49-68.e9
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -