Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice.
Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice.
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使用人源化小鼠中产生的肿瘤抗原特异性 T 细胞进行人类黑色素瘤免疫治疗
DOI：
10.18632/oncotarget.7044
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Yang YG
中科院分区：
文献类型：
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作者：
Hu Z;Xia J;Fan W;Wargo J;Yang YG
阻碍在临床前环境中探索过继免疫疗法的一个主要因素是肿瘤反应性人T细胞的有限可用性。在这里，我们开发了一种人源化小鼠模型，该模型允许大规模生产表达工程化黑素瘤抗原MART-1特异性TCR的人T细胞。通过移植人胎儿胸腺组织和用HLA I类限制性黑色素瘤抗原（MART-1）特异性TCR基因病毒转导的CD 34+细胞制备的人源化小鼠显示出MART-1-TCR+人T细胞的有效发育，其中主要是CD 8+细胞。重要的是，在这些小鼠中发育的MART-1-TCR+ CD 8 + T细胞能够在体内产生抗原特异性应答，如MART-1肽免疫后它们的增殖、表型转化和IFN-γ产生所证明的。此外，这些MART-1-TCR+ CD 8 + T细胞以HLA/抗原依赖性方式介导黑素瘤细胞的有效杀伤。体外扩增的MART-1-TCR+ CD 8 + T细胞的连续转移诱导了有效的抗肿瘤应答，IL-15治疗进一步增强了黑色素瘤受体的抗肿瘤应答。最后，MART-1特异性T细胞与雷帕霉素的短暂孵育与IL-15协同作用，导致转移性黑色素瘤受体的无瘤生存率显著提高。这些数据证明了使用人源化小鼠产生潜在无限来源的肿瘤特异性人类T细胞用于癌症免疫疗法的实验和临床前探索的实用性。这项研究还表明，雷帕霉素预处理肿瘤反应性T细胞联合IL-15给药可能是一种新的策略，以提高过继性T细胞治疗的疗效。
A major factor hindering the exploration of adoptive immunotherapy in preclinical settings is the limited availability of tumor-reactive human T cells. Here we developed a humanized mouse model that permits large-scale production of human T cells expressing the engineered melanoma antigen MART-1-specific TCR. Humanized mice, made by transplantation of human fetal thymic tissue and CD34+ cells virally-transduced with HLA class I-restricted melanoma antigen (MART-1)-specific TCR gene, showed efficient development of MART-1-TCR+ human T cells with predominantly CD8+ cells. Importantly, MART-1-TCR+CD8+ T cells developing in these mice were capable of mounting antigen-specific responses in vivo, as evidenced by their proliferation, phenotypic conversion and IFN-γ production following MART-1 peptide immunization. Moreover, these MART-1-TCR+CD8+ T cells mediated efficient killing of melanoma cells in an HLA/antigen-dependent manner. Adoptive transfer of in vitro expanded MART-1-TCR+CD8+ T cells induced potent antitumor responses that were further enhanced by IL-15 treatment in melanoma-bearing recipients. Finally, a short incubation of MART-1-specific T cells with rapamycin acted synergistically with IL-15, leading to significantly improved tumor-free survival in recipients with metastatic melanoma. These data demonstrate the practicality of using humanized mice to produce potentially unlimited source of tumor-specific human T cells for experimental and preclinical exploration of cancer immunotherapy. This study also suggests that pretreatment of tumor-reactive T cells with rapamycin in combination with IL-15 administration may be a novel strategy to improve the efficacy of adoptive T cell therapy.