肿瘤细胞治疗研究
英文原题：EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.
基于 T 细胞的免疫疗法已显示出治疗弥漫大 B 细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）的有效性，但预测疗效和了解耐药仍是一大挑战。
基于T细胞的免疫疗法已显示治疗弥漫性大B细胞淋巴瘤（DLBCL）和滤泡性淋巴瘤（FL）的疗效，但预测应答并理解耐药仍具挑战。为此，我们开发了能够反映人FL和DLBCL遗传学、表观遗传学及免疫学特征的同系模型。研究显示，EZH2抑制剂可重编程这些模型，使其重新表达T细胞参与相关基因，并变得高度免疫原性。EZH2抑制剂不会损害肿瘤控制性T细胞或CAR-T细胞，反而可减少调节性T细胞、促进记忆样CAR CD8表型并降低耗竭，从而减少肿瘤负荷。活体双光子成像显示，CAR-T细胞在肿瘤微环境中的募集及相互作用增加，改善了对淋巴瘤细胞的杀伤。因此，EZH2抑制除使淋巴瘤B细胞具有免疫原性外，还可直接作用于CAR-T细胞，提高其疗效。目前，正在两项临床试验中评估这一方法，以改善B细胞淋巴瘤患者免疫治疗结局（NCT05934838和NCT05994235）。
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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