Isshiki et al. developed syngeneic mouse models of FL and DLBCL to study inhibitors of the histone methyl-transferase enhancer of zeste 2 (EZH2), which mediates broad gene silencing, mostly by targeting tumor suppressor genes. EZH2 inhibition boosted lymphoma immunogenicity by upregulating expression of genes for mediators of cognate T cell interactions, making lymphomas more sensitive to anti-CD20xCD3 antibody and anti-CD19 CAR-T cell therapies. EZH2 inhibition also directly affected T cells, reducing Tregs and T cell exhaustion by promoting a memory phenotype. In the TME, EZH2 inhibition enhanced the duration and contact surface of CAR-T cell–lymphoma cell interactions.
Contributed by Paula Hochman
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.
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (2) Division of Hematology/Oncology, Department of Medic
Author Info: (1) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (2) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (3) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (4) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (5) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (6) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, Cornell University, New York, NY, USA. (8) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (9) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (10) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (11) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (12) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA; Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and Rockefeller University, New York City, NY, USA. (13) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA. (14) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (15) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (16) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel. (17) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 76100, Israel. (18) Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (19) Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (20) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (21) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA. (22) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (23) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, USA. (24) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (25) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: web2002@med.cornell.edu.
