美国康奈尔大学Wendy Béguelin研究组发现，EZH2抑制通过诱导淋巴瘤免疫原性和改善T细胞功能增强T细胞免疫疗法。相关论文于2024年12月5日在线发表于国际学术期刊《癌细胞》。

研究人员表示，基于T细胞的免疫疗法已被证明在治疗弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）中有效，但预测疗效和理解耐药性仍然是挑战。

为了解决这一问题，研究人员开发了反映人类FL和DLBCL的遗传学、表观遗传学和免疫学的同种异体模型。研究表明，EZH2抑制剂能够重新编程这些模型，使其重新表达T细胞参与基因，从而使其具有较高的免疫原性。EZH2抑制剂不会损害肿瘤控制T细胞或CAR-T细胞。

相反，它们减少了调节性T细胞的数量，促进了记忆型嵌合抗原受体（CAR）CD8表型，并减少了耗竭，最终导致肿瘤负荷减少。活体双光子成像显示，CAR-T细胞在肿瘤微环境中的招募和相互作用增加，改善了对淋巴瘤细胞的杀伤作用。

因此，EZH2抑制通过对CAR-T细胞的直接作用以及使淋巴瘤B细胞具备免疫原性，增强了CAR-T细胞的疗效。目前这一方法正在两个临床试验中进行评估（NCT05934838和NCT05994235）以改善B细胞淋巴瘤患者的免疫治疗效果。

附：英文原文

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

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

Issue&Volume: 2024-12-05

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.

DOI: 10.1016/j.ccell.2024.11.006

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00441-0