Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor
Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor
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DOI：
10.1038/nbt0102-70
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发表时间：
2002-01-01
影响因子：
46.9
通讯作者：
Sadelain, M
中科院分区：
文献类型：
--
作者：
Maher, J;Brentjens, RJ;Sadelain, M
人工受体为将T淋巴细胞靶向肿瘤抗原提供了一种有前景的方法。然而，到目前为止所描述的受体要么单独产生激活信号，要么单独产生共刺激信号，从而限制了转基因细胞所能实现的功能范围。在此我们表明，表达针对前列腺特异性膜抗原（PSMA）且包含T细胞受体 - ξ（TCR ξ）和CD28信号元件的融合受体的人原代T淋巴细胞能有效裂解表达PSMA的肿瘤细胞。当受到细胞表面PSMA刺激时，经逆转录病毒转导的淋巴细胞会强劲增殖，在三周内扩增超过2个对数级，并产生大量白细胞介素 - 2（IL - 2）。重要的是，扩增的细胞群保留了其抗原特异性的细胞溶解活性。这些数据表明，同时包含TCR和CD28信号部分的融合受体是能够重定向和扩增人T细胞反应的有效分子。这些发现对癌症的过继性免疫治疗具有重要意义，特别是对于那些不表达主要组织相容性复合体抗原和共刺激分子的肿瘤细胞而言。
Artificial receptors provide a promising approach to target T lymphocytes to tumor antigens. However, the receptors described thus far produce either an activation or a co-stimulatory signal alone, thus limiting the spectrum of functions accomplished by the genetically modified cells. Here we show that human primary T lymphocytes expressing fusion receptors directed to prostate-specific membrane antigen (PSMA) and containing combined T-cell receptor-xi (TCR xi), and CD28 signaling elements, effectively lyse tumor cells expressing PSMA. When stimulated by cell-surface PSMA, retrovirally transduced lymphocytes undergo robust proliferation, expanding by more than 2 logs in three weeks, and produce large amounts of interleukin-2 (IL-2). Importantly, the amplified cell populations retain their antigen-specific cytolytic activity. These data demonstrate that fusion receptors containing both TCR and CD28 signaling moieties are potent molecules able to redirect and amplify human T-cell responses, These findings have important implications for adoptive immunotherapy of cancer, especially in the context of tumor cells that fail to express major histocompatibility complex antigens and co-stimulatory molecules.