Generation of highly proliferative, rejuvenated cytotoxic T cell clones through pluripotency reprogramming for adoptive immunotherapy
Generation of highly proliferative, rejuvenated cytotoxic T cell clones through pluripotency reprogramming for adoptive immunotherapy
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DOI：
10.1016/j.ymthe.2021.05.016
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发表时间：
2021-10-06
影响因子：
12.4
通讯作者：
Kaneko, Shin
中科院分区：
文献类型：
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作者：
Kawai, Yohei;Kawana-Tachikawa, Ai;Kaneko, Shin
过继免疫疗法已成为治疗癌症和慢性感染的有效方法。目前，提供持久免疫力的大量 T 细胞的产生面临着衰竭和分化相关衰老的挑战，这在体外克隆和扩增过程中不可避免地出现。为了解决这些问题，一些研究提出了一种诱导多能干细胞 (iPSC) 介导的复兴策略，以恢复耗尽/衰老的 T 细胞克隆的活力。由于通过常用的单层系统产生的 iPSC 衍生的细胞毒性 T 淋巴细胞 (iPSC-CTL) 具有不利的先天特征，例如异常的自然杀伤 (NK) 活性和有限的复制潜力，因此我们修改了再分化培养物以生成 CD8 α beta(+)CD5(+) CCR7(+)CD45RA(+)CD56(-) 适应性 iPSC-CTL。修饰后的 iPSC-CTL 表现出早期记忆表型，包括高复制能力和产生有效效应细胞的能力。在使用优化的细胞因子混合物的扩增培养中，iPSC-CTL 在无饲养条件下增殖超过 10(15) 倍。我们的早期记忆 iPSC-CTL 的再分化和扩展包可以为自体和同种异体免疫疗法提供记忆和效应 T 细胞。
Adoptive immunotherapy has emerged as a powerful approach to cure cancer and chronic infections. Currently, the generation of a massive number of T cells that provide long-lasting immunity is challenged by exhaustion and differentiation-associated senescence, which inevitably arise during in vitro cloning and expansion. To circumvent these problems, several studies have proposed an induced pluripotent stem cell (iPSC)-mediated rejuvenation strategy to revitalize the exhausted/senescent T cell clones. Because iPSC-derived cytotoxic T lymphocytes (iPSC-CTLs) generated via commonly used monolayer systems have unfavorable, innate-like features such as aberrant natural killer (NK) activity and limited replication potential, we modified the redifferentiation culture to generate CD8 alpha beta(+)CD5(+) CCR7(+)CD45RA(+)CD56(-)-adaptive iPSC-CTLs. The modified iPSC-CTLs exhibited early memory phenotype, including high replicative capacity and the ability to give rise to potent effector cells. In expansion culture with an optimized cytokine cocktail, iPSC-CTLs proliferated more than 10(15)-fold in a feeder-free condition. Our redifferentiation and expansion package of early memory iPSC-CTLs could supply memory and effector T cells for both autologous and allogeneic immunotherapies.