Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells.
Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells.
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DOI：
10.1186/1479-5876-2-41
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发表时间：
2004-11-26
影响因子：
7.4
通讯作者：
Plautz, Gregory E
中科院分区：
文献类型：
--
作者：
Wang, Li-Xin;Huang, Wen-Xin;Plautz, Gregory E
T细胞介导的癌症免疫疗法是剂量依赖性的，并且最佳地需要抗原特异性CD 4+和CD 8 + T细胞的参与。在这里，我们分离出肿瘤致敏的T细胞，并在体外使用导致CD 4+或CD 8+亚群超过108倍的数值过度扩张的条件激活它们，同时保留它们在体内治疗功效的能力。分离鼠肿瘤引流淋巴结（TDLN）细胞以纯化CD 62 L低亚群或其CD 4+亚群。然后通过多个循环的抗CD 3活化来增殖细胞，对于CD 8+亚群，用IL-2 + IL-7，或对于CD 4+亚群，用IL-7 + IL-23。广泛的TCR V β家族库在整个过度膨胀过程中得以维持，这与起始群体相似。过度扩增的CD 8 + T细胞的连续转移以免疫特异性方式消除了已建立的肺转移，而不需要辅助IL-2。过度扩增的CD 4 + T细胞治愈了颅内或皮下部位的已建立肿瘤，这些肿瘤对单独的CD 8 + T细胞不敏感。由于转移瘤内的可及性和抗原呈递根据解剖部位而变化，因此维持广泛的CD 4+和CD 8 + T效应细胞库将增强过继免疫治疗的总体全身疗效。
T cell-mediated cancer immunotherapy is dose dependent and optimally requires participation of antigen-specific CD4+ and CD8+ T cells. Here, we isolated tumor-sensitized T cells and activated them in vitro using conditions that led to greater than 108-fold numerical hyperexpansion of either the CD4+ or CD8+ subset while retaining their capacity for in vivo therapeutic efficacy. Murine tumor-draining lymph node (TDLN) cells were segregated to purify the CD62Llow subset, or the CD4+ subset thereof. Cells were then propagated through multiple cycles of anti-CD3 activation with IL-2 + IL-7 for the CD8+ subset, or IL-7 + IL-23 for the CD4+ subset. A broad repertoire of TCR Vbeta families was maintained throughout hyperexpansion, which was similar to the starting population. Adoptive transfer of hyper-expanded CD8+ T cells eliminated established pulmonary metastases, in an immunologically specific fashion without the requirement for adjunct IL-2. Hyper-expanded CD4+ T cells cured established tumors in intracranial or subcutaneous sites that were not susceptible to CD8+ T cells alone. Because accessibility and antigen presentation within metastases varies according to anatomic site, maintenance of a broad repertoire of both CD4+ and CD8+ T effector cells will augment the overall systemic efficacy of adoptive immunotherapy.