Wang Li-Xin, Huang Wen-Xin, Graor Hallie, Cohen Peter A, Kim Julian A, Shu Suyu, Plautz Gregory E
Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH, USA.
J Transl Med. 2004 Nov 26;2(1):41. doi: 10.1186/1479-5876-2-41.
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.
T细胞介导的癌症免疫疗法具有剂量依赖性，并且最佳情况下需要抗原特异性CD4+和CD8+ T细胞的参与。在此，我们分离了肿瘤致敏T细胞，并在体外使用能使CD4+或CD8+亚群在数量上超扩增超过108倍的条件激活它们，同时保留其体内治疗功效的能力。对小鼠肿瘤引流淋巴结（TDLN）细胞进行分离，以纯化CD62Llow亚群或其CD4+亚群。然后，对于CD8+亚群，通过用IL-2 + IL-7进行抗CD3激活的多个循环来扩增细胞；对于CD4+亚群，则通过IL-7 + IL-23进行扩增。在整个超扩增过程中，TCR Vβ家族的广泛谱系得以维持，这与起始群体相似。过继转移超扩增的CD8+ T细胞以免疫特异性方式消除了已形成的肺转移灶，而无需辅助IL-2。超扩增的CD4+ T细胞治愈了颅内或皮下部位已形成的肿瘤，这些部位单独使用CD8+ T细胞是无效的。由于转移灶内的可及性和抗原呈递因解剖部位而异，维持广泛的CD4+和CD8+ T效应细胞谱系将增强过继免疫疗法的整体全身疗效。
