肿瘤细胞治疗研究
英文原题：BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma.
胶质母细胞瘤（GBM）是最致命的脑部恶性肿瘤，尚无有效治疗方法。
胶质母细胞瘤（GBM）是致死率最高的脑部恶性肿瘤，目前缺乏有效治疗。本研究报告，靶向表皮生长因子受体的CAR-T 细胞（EGFR CAR-T）可在体外有效抑制 GBM 细胞生长，也可抑制小鼠体内由 GBM 细胞系及患者来源细胞形成的异种移植瘤。然而，小鼠很快对 EGFR CAR-T 治疗产生耐药，限制其临床应用潜力。为寻找提高 EGFR CAR-T 疗效的方法，研究者对与 EGFR CAR-T 共孵育的 GBM 细胞进行基因组和转录组分析，发现大量基因（包括免疫抑制基因）及其附近增强子被激活。BRD4 是作用于启动子和增强子的表观遗传调节因子，对这些免疫抑制基因的激活必不可少。因此，使用 JQ1 抑制 BRD4 可阻断免疫抑制基因激活。EGFR CAR-T 联合 JQ1 可抑制小鼠 GBM 生长和转移，并延长生存期。研究证明，靶向表观遗传调控因子以调节转录，可提高包括 CAR-T 在内的免疫治疗疗效，为临床治疗 GBM 提供了新途径。
Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments. Here, we reported that epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) were effective in suppressing the growth of GBM cells in vitro and xenografts derived from GBM cell lines and patients in mice. However, mice soon acquired resistance to EGFR CAR-T cell treatment, limiting its potential use in the clinic. To find ways to improve the efficacy of EGFR CAR-T cells, we performed genomics and transcriptomics analysis for GBM cells incubated with EGFR CAR-T cells and found that a large cohort of genes, including immunosuppressive genes, as well as enhancers in vicinity are activated. BRD4, an epigenetic modulator functioning on both promoters and enhancers, was required for the activation of these immunosuppressive genes. Accordingly, inhibition of BRD4 by JQ1 blocked the activation of these immunosuppressive genes. Combination therapy with EGFR CAR-T cells and JQ1 suppressed the growth and metastasis of GBM cells and prolonged survival in mice. We demonstrated that transcriptional modulation by targeting epigenetic regulators could improve the efficacy of immunotherapy including CAR-T, providing a therapeutic avenue for treating GBM in the clinic.
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