BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models
BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models
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DOI：
10.1172/jci86437
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Hirano, Naoto
中科院分区：
文献类型：
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作者：
Kagoya, Yuki;Nakatsugawa, Munehide;Hirano, Naoto
过继免疫疗法是晚期癌症患者的一种潜在的治疗方法。然而，在输注前抗肿瘤T细胞的体外扩增不可避免地导致向效应T细胞的分化，并损害过继转移后的持久性。表观遗传谱在免疫细胞分化、增殖和功能过程中调节关键转录因子的基因表达。通过综合筛选具有明确表观遗传靶点的化学探针，我们发现JQ1，一种bromodomain和外端基元（outer -terminal motif， BET）蛋白抑制剂，维持CD8(+)T细胞具有干细胞样和中枢记忆T细胞的功能特性。在机制上，BET蛋白BRD4直接调节CD8(+)T细胞中转录因子BATF的表达，这与T细胞向效应记忆表型的分化有关。在小鼠T细胞受体和嵌合抗原受体基因治疗模型中，jq1处理的T细胞表现出增强的持久性和抗肿瘤作用。此外，我们发现组蛋白乙酰转移酶p300支持BRD4募集到BATF启动子区域，p300抑制类似地增强了过继转移T细胞的抗肿瘤作用。这些结果表明，靶向BRD4-p300信号级联支持产生用于过继免疫治疗的优质抗肿瘤T细胞移植物。
Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8(+)T cells with functional properties of stem cell-like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in CD8(+)T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1-treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy.