EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.

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Tác giả: Wendy Béguelin, Renier J Brentjens, Winson Cai, Sebastián E Carrasco, Amy Chadburn, Xi Chen, Vigneshwari Easwar Kumar, Ofir Griess, Johana Gutierrez, Giorgio Inghirami, Yusuke Isshiki, Ioannis Karagiannidis, Peter Martin, Ari M Melnick, Cem Meydan, Henna Nam, Madhu M Ouseph, Patrizia Porazzi, Marco Ruella, Efrat Shema, Hao Shen, Matt Teater, Min Xia, Samuel Yamshon, Roberta Zappasodi

Ngôn ngữ: eng

Ký hiệu phân loại: 527 Celestial navigation

Thông tin xuất bản: United States : Cancer cell , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 60163

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.
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