美国宾夕法尼亚大学Marco Ruella研究团队发现，EZH1/EZH2抑制增强对多种癌症模型的过继性T细胞免疫治疗。该项研究成果发表在2025年2月20日出版的《癌细胞》上。

研究团队假设抑制肿瘤驱动因子的甲基转移酶EZH2和EZH1可以通过将癌细胞重新连接到更免疫原性的状态来增强ACT。在人B细胞淋巴瘤中，EZH2抑制剂（tazemetostat）通过增强活化、扩增和肿瘤浸润来提高抗CD19 CAR-T的疗效。在机制上，tazemetostat治疗的肿瘤显示出与粘附、B细胞活化和炎症反应相关的基因上调，并增加了对CAR-T的渴望。

此外，tazemetostat提高了CAR-和TCR工程T细胞治疗多种液体（骨髓瘤和急性髓性白血病）和实体（肉瘤、卵巢癌和前列腺癌）癌症的疗效。最后，EZH1/EZH2联合抑制（valemetostat）进一步提高了CAR-T在多种癌症中的疗效和扩展。本研究表明EZH1/2抑制在液体和实体癌症的临床前模型中使肿瘤重编程到更具免疫原性的状态，并增强ACT。

据介绍，肿瘤对嵌合抗原受体T细胞（CAR-T）和过继细胞免疫疗法（ACTs）的耐药性是临床的主要挑战。

附：英文原文

Title: EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models

Author: Patrizia Porazzi, Siena Nason, Ziqi Yang, Alberto Carturan, Guido Ghilardi, Puneeth Guruprasad, Ruchi P. Patel, Melody Tan, Anushka Anant Padmanabhan, Jean Lemoine, Eugenio Fardella, Yunlin Zhang, Raymone Pajarillo, Linhui Chen, Ositadimma Ugwuanyi, Kelly Markowitz, Devora Delman, Mathew G. Angelos, Olga Shestova, Yusuke Isshiki, Tatiana Blanchard, Wendy Béguelin, Ari M. Melnick, Gerald P. Linette, Gregory L. Beatty, Beatriz M. Carreno, Ivan Cohen, Luca Paruzzo, Stephen J. Schuster, Marco Ruella

Issue&Volume: 2025-02-20

Abstract: Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers’ methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.

DOI: 10.1016/j.ccell.2025.01.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00031-5