PDF(Pubmed)
Abstract：
Adoptive immunotherapy, in which tumor-reactive T cells are prepared in vitro for adoptive transfer to the patient, can induce an objective clinical response in specific types of cancer. In particular, chimeric antigen receptor (CAR)-redirected T-cell therapy has shown robust responses in hematologic malignancies. However, its efficacy against most of the other tumors is still insufficient, which remains an unmet medical need. Accumulating evidence suggests that modifying specific genes can enhance antitumor T-cell properties. Epigenetic factors have been particularly implicated in the remodeling of T-cell functions, including changes to dysfunctional states such as terminal differentiation and exhaustion. Genetic ablation of key epigenetic molecules prevents the dysfunctional reprogramming of T cells and preserves their functional properties.Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-based gene editing is a valuable tool to enable efficient and specific gene editing in cultured T cells. A number of studies have already identified promising targets to improve the therapeutic efficacy of CAR-T cells using genome-wide or focused CRISPR screening. In this review, we will present recent representative findings on molecular insights into T-cell dysfunction and how genetic modification contributes to overcoming it. We will also discuss several technical advances to achieve efficient gene modification using the CRISPR and other novel platforms.
摘要：
过继免疫疗法,其中在体外制备肿瘤反应性T细胞用于过继转移给患者，可以在特定类型的癌症中诱导客观的临床反应。特别是,嵌合抗原受体(CAR)重定向T细胞治疗在血液系统恶性肿瘤中显示出稳健的应答.然而,它对大多数其他肿瘤的疗效仍然不足，这仍然是一个未满足的医疗需求。越来越多的证据表明，修饰特定基因可以增强抗肿瘤T细胞的特性。表观遗传因素特别涉及T细胞功能的重塑，包括功能失调状态的变化，如终末分化和疲惫。关键表观遗传分子的遗传消融可防止T细胞的功能失调重编程并保留其功能特性。聚集,规则间隔,基于短回文重复序列(CRISPR)/CRISPR相关蛋白(Cas)的基因编辑是在培养的T细胞中实现高效和特异性基因编辑的有价值的工具.许多研究已经确定了有希望的靶标，以使用全基因组或集中的CRISPR筛选来提高CAR-T细胞的治疗效果。在这次审查中,我们将介绍有关T细胞功能障碍的分子见解以及基因修饰如何有助于克服T细胞功能障碍的最新代表性发现。我们还将讨论使用CRISPR和其他新型平台实现有效基因修饰的若干技术进展。
