肿瘤细胞治疗研究
英文原题：BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia.
程序性细胞死亡受体-1（PD-1）的持续表达与T细胞耗竭相关，而阻断PD-1通路是治疗多种癌症的有效免疫治疗策略。
程序性细胞死亡受体-1（PD-1）的持续表达与T细胞耗竭相关，而阻断PD-1通路是治疗多种癌症的有效免疫治疗策略。然而，应答率有限，许多患者未能获得持久应答。因此，寻找能够改善抗肿瘤免疫的额外策略十分重要。在此，我们报道溴结构域和超末端结构域（BET）抑制剂JQ1可抑制Jurkat T细胞、原代T细胞及T细胞耗竭模型中的PD-1表达。此外，JQ1显著降低急性髓系白血病（AML）患者T细胞中PD-1和T细胞免疫球蛋白黏蛋白结构域包含-3（Tim-3）的表达，并促进细胞因子分泌。与此一致，经BET抑制剂处理的CD19-CAR T和CD123-CAR T细胞具有增强的抗白血病效力且抵抗耗竭。在机制上，BRD4结合于NFAT2和PDCD1（编码PD-1）启动子，而NFAT2结合于PDCD1和HAVCR2（编码Tim-3）启动子。经JQ1处理的T细胞显示NFAT2、PD-1和Tim-3表达下调。此外，BET抑制剂抑制AML细胞系和原代AML细胞中程序性死亡配体1（PD-L1）的表达及细胞生长。我们还证明，在MLL-AF9 AML小鼠模型和Nalm6（B细胞急性淋巴细胞白血病细胞）荷瘤小鼠白血病模型中，JQ1治疗可抑制白血病进展、降低T细胞PD-1/Tim-3表达并延长生存期。综上所述，BET抑制通过调控PD-1/PD-L1表达改善抗白血病免疫，并直接抑制AML细胞，这为BET抑制在癌症治疗中的多重效应提供了新见解。
Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.
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