Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy.
Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy.
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DOI：
10.1038/ncomms15338
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发表时间：
2017-05-22
影响因子：
16.6
通讯作者：
Yoshimura A
中科院分区：
文献类型：
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作者：
Kondo T;Morita R;Okuzono Y;Nakatsukasa H;Sekiya T;Chikuma S;Shichita T;Kanamori M;Kubo M;Koga K;Miyazaki T;Kassai Y;Yoshimura A
过继T细胞免疫治疗是一种很有前途的癌症治疗方法。干细胞记忆T细胞(干细胞Memory T cell，TSCM)被认为是一类长寿、高增殖的记忆T细胞。CD8+TSCM细胞可以通过Wnt信号在体外由原始CD8+T细胞产生，然而，目前还没有从激活的或记忆的T细胞诱导TSCM细胞的方法。在这里，我们展示了一种策略，通过与表达Notch配体的基质细胞共培养，在体外从小鼠和人类的激活的CD4+和CD8+T细胞中产生TSCM样细胞(iTSCM细胞)。ITSCM细胞失去PD-1和CTLA-4的表达，并在重新刺激后产生大量的肿瘤特异性效应细胞。因此，该方法可用于产生抗原特异性效应T细胞用于过继免疫治疗。肿瘤特异性T细胞可以在体外扩增并过继转移用于治疗，但这一策略受到短期T细胞群体诱导的限制。在这里，作者激活了培养的小鼠或人类T细胞中的Notch信号，导致产生了能够对抗小鼠肿瘤的长寿干细胞记忆T细胞群体。
Adoptive T-cell immunotherapy is a promising approach to cancer therapy. Stem cell memory T (TSCM) cells have been proposed as a class of long-lived and highly proliferative memory T cells. CD8+ TSCM cells can be generated in vitro from naive CD8+ T cells via Wnt signalling; however, methods do not yet exist for inducing TSCM cells from activated or memory T cells. Here, we show a strategy for generating TSCM-like cells in vitro (iTSCM cells) from activated CD4+ and CD8+ T cells in mice and humans by coculturing with stromal cells that express a Notch ligand. iTSCM cells lose PD-1 and CTLA-4 expression, and produce a large number of tumour-specific effector cells after restimulation. This method could therefore be used to generate antigen-specific effector T cells for adoptive immunotherapy. Tumour-specific T cells can be expanded in vitro and adoptively transferred for therapy, but this strategy is limited by induction of short-lived T cell populations. Here the authors activate Notch signalling in cultured mouse or human T cells, resulting in the production of a long-lived stem cell memory T cell population that can fight tumours in mice.