肿瘤细胞治疗研究
英文原题：EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models.
本研究表明，EZH1/2抑制可将肿瘤重编程为更具免疫原性的状态，并在血液肿瘤和实体瘤的临床前模型中增强ACT的疗效。
肿瘤对CAR-T 细胞以及总体上对过继细胞免疫治疗（ACT）的耐药性是临床上的一大挑战。我们假设，抑制肿瘤驱动因子的甲基转移酶 EZH2 和 EZH1 可通过将癌细胞重编程为更具免疫原性的状态来增强 ACT。在人 B 细胞淋巴瘤中，EZH2 抑制（tazemetostat）通过增强活化、扩增和肿瘤浸润提高了抗 CD19 CAR-T 的疗效。在机制上，经 tazemetostat 处理的肿瘤显示与黏附、B 细胞活化和炎症反应相关的基因上调，并且对 CAR-T 的亲和力增加。此外，tazemetostat 提高了 CAR 和 TCR 工程化 T 细胞在多种血液系统肿瘤（骨髓瘤和急性髓系白血病）和实体瘤（肉瘤、卵巢癌和前列腺癌）中的疗效。最后，联合抑制 EZH1/EZH2（valemetostat）进一步提升了 CAR-T 在多种癌症中的疗效和扩增。本研究表明，EZH1/2 抑制可将肿瘤重编程为更具免疫原性的状态，并在血液系统肿瘤和实体瘤的临床前模型中增强 ACT。
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.
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