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.

中文翻译：

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EZH2 抑制通过诱导淋巴瘤免疫原性和改善 T 细胞功能来增强 T 细胞免疫治疗


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） 方面有效，但预测反应和了解耐药性仍然是一个挑战。为了解决这个问题，我们开发了反映人类 FL 和 DLBCL 的遗传学、表观遗传学和免疫学的同基因模型。我们表明 EZH2 抑制剂对这些模型进行重编程以重新表达 T 细胞结合基因并使它们具有高度免疫原性。EZH2 抑制剂不会伤害肿瘤控制 T 细胞或 CAR-T 细胞。相反，它们会减少调节性 T 细胞，促进记忆嵌合抗原受体 （CAR） CD8 表型，并减少耗竭，从而减少肿瘤负荷。活体 2 光子成像显示肿瘤微环境中 CAR-T 募集和相互作用增加，改善淋巴瘤细胞杀伤。因此，EZH2 抑制除了使淋巴瘤 B 细胞具有免疫原性外，还通过直接影响 CAR-T 细胞来增强 CAR-T 细胞的功效。这种方法目前正在 NCT05934838 和 NCT05994235 两项临床试验中进行评估，以改善 B 细胞淋巴瘤患者的免疫治疗结果。