Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma
Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma
复制标题
瘤内注射树突状细胞结合局部热疗对晚期黑色素瘤患者产生全身抗肿瘤作用
DOI：
10.1002/ijc.22551
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发表时间：
2007-06-01
影响因子：
6.4
通讯作者：
Yang, Zhi
中科院分区：
文献类型：
--
作者：
Guo, Jun;Zhu, Jun;Yang, Zhi
树突状细胞(DC)是一种强大的抗原提呈细胞，可以呈递热休克蛋白(HSPs)伴随的肿瘤抗原，而局部热疗(LHT)可以增加HSPs的表达。在这项研究中，我们确定LHT后瘤内注射未成熟DC(LHT+IT-DC)是否能诱导晚期黑色素瘤患者的全身抗肿瘤免疫，并探讨其潜在的免疫学机制。患者被随机分配到瘤内给予自体未成熟DC三周一次，其中有(LHT+IT-DC，ARM A，n=9)或没有(IT-DC，ARM B，n=9)LHT。我们的结果表明，没有3/4级毒性。A组进展时间(TTP)为5个月，显著长于B组(2个月，p<；0.05)。然而，两组患者的总体生存时间(13个月与6个月，p>；0.05)无统计学差异。我们的ELISPOT分析显示，在手臂A中黑色素瘤特异性干扰素-γ的产生显著增加，这表明LHT+IT-DC在诱导细胞毒性T淋巴细胞(CTL)方面比单独使用IT-DC更有效。此外，我们检测到第一次LHT后4小时HSPs表达增加，第一次LHT+IT-DC治疗24小时后Th1/Th2趋化因子产生增加，DC向传入淋巴结迁移促进，第三次DC注射48小时后调节性T细胞(CD4(+)CD25(+))的渗透减少，活性CTL(CD8(+)CD28(+))的渗透增加。因此，LHT+IT-DC能有效诱导晚期黑色素瘤患者的特异性抗肿瘤免疫，促进Th1极化的免疫反应。(C)2007年Wiley-Liss，Inc.
Dendritic cells (DC) are potent antigen-presenting cells that can present tumor antigens chaperoned by heat shock proteins (HSPs), while local hyperthermia (LHT) can increase the expression of HSPs. In this study, we determine if intratumoral injection of immature DC after LHT (LHT+IT-DC) induces systemic antitumor immunity in patients with advanced melanoma, and investigate the potential immunological mechanisms involved in the treatments. Patients were randomly assigned to intratumoral administration of autologous immature DC triweekly, with (LHT+IT-DC, arm A, n = 9) or without (IT-DC, arm B, n = 9) LHT. Our results showed that there were no grade 3/4 toxicities. The time to progress (TTP) of arm A was 5 months, significantly longer than that in arm B (2 months, p < 0.05). However, the overall survival time had no statistical difference (13 months vs. 6 months, p > 0.05) between the 2 groups. Our ELISPOT assay showed a significantly increased melanoma-specific IFN-gamma production in arm A, suggesting that LHT+IT-DC was more effective in the induction of cytotoxic T lymphocytes (CTL) than IT-DC alone. Furthermore, we detected an increased HSPs expression 4 hr after the first LHT, an enhanced Th1/Th2 chemokines production 24 hr after the first LHT+IT-DC treatment, a promoted migration of DC to afferent lymph nodes, and a decreased infiltration of regulatory T cells (CD4(+)CD25(+)) and an increased infiltration of active CTL (CD8(+)CD28(+)) 48 hr after the third DC injection in arm A patients. Therefore, LHT+IT-DC can induce effective specific antitumor immunity and facilitate a Th1-polarized immune response in patients with advanced melanoma. (c) 2007 Wiley-Liss, Inc.