Hegmans Joost P J J, Hemmes Annabrita, Aerts Joachim G, Hoogsteden Henk C, Lambrecht Bart N
Department of Pulmonary Medicine, Erasmus MC, H-Ee2253a, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Am J Respir Crit Care Med. 2005 May 15;171(10):1168-77. doi: 10.1164/rccm.200501-057OC. Epub 2005 Mar 11.
Exploiting the immunostimulatory capacities of dendritic cells holds great promise for cancer immunotherapy. Currently, dendritic cell-based immunotherapy is evaluated clinically in a number of malignancies, including melanoma and urogenital and lung cancer, showing variable but promising results.
To evaluate if pulsed dendritic cells induce protective immunity against malignant mesothelioma in a mouse model.
Malignant mesothelioma was induced in mice by intraperitoneal injection of the AB1 mesothelioma cell line, leading to death within 28 days. For immunotherapy, dendritic cells were pulsed overnight either with AB1 tumor cell line lysate, AB1-derived exosomes, or ex vivo AB1 tumor lysate, and injected either before (Days -14 and -7) at the day of (Day 0) or after (Days +1 and +8) tumor implantation.
Mice receiving tumor lysate-pulsed dendritic cells before tumor implantation demonstrated protective antitumor immunity with prolonged survival (> 3 months) and even resisted secondary tumor challenge. Tumor protection was associated with strong tumor-specific cytotoxic T-lymphocyte responses. Adoptive transfer of splenocytes or purified CD8+ T lymphocytes transferred tumor protection to unimmunized mice in vivo. When given after tumor implantation in a therapeutic setting, pulsed dendritic cells prevented mesothelioma outgrowth. With higher tumor load and delayed administration after tumor implantation, dendritic cells were no longer effective.
We demonstrate in this murine model that immunotherapy using pulsed dendritic cells may emerge as a powerful tool to control mesothelioma outgrowth. In the future, immunotherapy using dendritic cells could be used as adjuvant to control local recurrence after multimodality treatment for malignant mesothelioma.
利用树突状细胞的免疫刺激能力在癌症免疫治疗中具有巨大潜力。目前，基于树突状细胞的免疫疗法正在多种恶性肿瘤中进行临床评估，包括黑色素瘤、泌尿生殖系统肿瘤和肺癌，显示出不同但有希望的结果。
评估脉冲树突状细胞是否能在小鼠模型中诱导针对恶性间皮瘤的保护性免疫。
通过腹腔注射AB1间皮瘤细胞系在小鼠中诱导恶性间皮瘤，导致小鼠在28天内死亡。对于免疫治疗，树突状细胞用AB1肿瘤细胞系裂解物、AB1来源的外泌体或体外AB1肿瘤裂解物过夜脉冲处理，并在肿瘤植入前（第-14天和-7天）、植入当天（第0天）或植入后（第+1天和+8天）注射。
在肿瘤植入前接受肿瘤裂解物脉冲处理的树突状细胞的小鼠表现出保护性抗肿瘤免疫，生存期延长（>3个月），甚至抵抗二次肿瘤攻击。肿瘤保护与强烈的肿瘤特异性细胞毒性T淋巴细胞反应相关。脾细胞或纯化的CD8+T淋巴细胞的过继转移在体内将肿瘤保护转移给未免疫的小鼠。在治疗环境中肿瘤植入后给予脉冲树突状细胞时，可防止间皮瘤生长。随着肿瘤负荷增加和肿瘤植入后给药延迟，树突状细胞不再有效。
我们在这个小鼠模型中证明，使用脉冲树突状细胞的免疫疗法可能成为控制间皮瘤生长的有力工具。未来，使用树突状细胞的免疫疗法可作为辅助手段，用于控制恶性间皮瘤多模式治疗后的局部复发。
