Powell Daniel J, Dudley Mark E, Robbins Paul F, Rosenberg Steven A
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
Blood. 2005 Jan 1;105(1):241-50. doi: 10.1182/blood-2004-06-2482. Epub 2004 Sep 2.
In humans, the pathways of memory T-cell differentiation remain poorly defined. Recently, adoptive cell transfer (ACT) of tumor-reactive T lymphocytes to metastatic melanoma patients after nonmyeloablative chemotherapy has resulted in persistence of functional, tumor-reactive lymphocytes, regression of disease, and induction of melanocyte-directed autoimmunity in some responding patients. In the current study, longitudinal phenotypic analysis was performed on melanoma antigen-specific CD8+ T cells during their transition from in vitro cultured effector cells to long-term persistent memory cells following ACT to 6 responding patients. Tumor-reactive T cells used for therapy were generally late-stage effector cells with a CD27Lo CD28Lo CD45RA- CD62 ligand- (CD62L-) CC chemokine receptor 7- (CCR7-) interleukin-7 receptor alphaLo (IL-7RalphaLo) phenotype. After transfer, rapid up-regulation and continued expression of IL-7Ralpha in vivo suggested an important role for IL-7R in immediate and long-term T-cell survival. Although the tumor antigen-specific T-cell population contracted between 1 and 4 weeks after transfer, stable numbers of CD27+)CD28+ tumor-reactive T cells were maintained, demonstrating their contribution to the development of long-term, melanoma-reactive memory CD8+ T cells in vivo. At 2 months after transfer, melanoma-reactive T cells persisted at high levels and displayed an effector memory phenotype, including a CD27+ CD28+ CD62L- CCR7- profile, which may explain in part their ability to mediate tumor destruction.
在人类中，记忆性T细胞分化的途径仍未明确界定。最近，在非清髓性化疗后将肿瘤反应性T淋巴细胞过继性细胞转移（ACT）至转移性黑色素瘤患者体内，已导致功能性肿瘤反应性淋巴细胞持续存在、疾病消退，并在一些有反应的患者中诱导了针对黑素细胞的自身免疫。在本研究中，对6例有反应患者进行ACT后，在黑色素瘤抗原特异性CD8⁺T细胞从体外培养的效应细胞转变为长期持续存在的记忆细胞的过程中进行了纵向表型分析。用于治疗的肿瘤反应性T细胞通常是具有CD27Lo CD28Lo CD45RA- CD62配体（CD62L-）CC趋化因子受体7-（CCR7-）白细胞介素-7受体αLo（IL-7RαLo）表型的晚期效应细胞。转移后，IL-7Rα在体内迅速上调并持续表达，提示IL-7R在T细胞的即刻和长期存活中起重要作用。尽管肿瘤抗原特异性T细胞群体在转移后1至4周内有所收缩，但CD27⁺CD28⁺肿瘤反应性T细胞的数量保持稳定，表明它们在体内对长期黑色素瘤反应性记忆CD8⁺T细胞的发育有贡献。转移后2个月，黑色素瘤反应性T细胞高水平持续存在，并表现出效应记忆表型，包括CD27⁺ CD28⁺ CD62L- CCR7-特征，这可能部分解释了它们介导肿瘤破坏的能力。
