黑色素瘤细胞裂解物诱导治疗性人树突状细胞 CCR7 的表达和体内向引流淋巴结的迁移。
Melanoma cell lysate induces CCR7 expression and in vivo migration to draining lymph nodes of therapeutic human dendritic cells.
机构信息
Millennium Institute on Immunology and Immunotherapy, University of Chile, Santiago, Chile; Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago, Chile.
出版信息
Immunology. 2014 Jul;142(3):396-405. doi: 10.1111/imm.12264.
We have previously reported a novel method for the production of tumour-antigen-presenting cells (referred to as TAPCells) that are currently being used in cancer therapy, using an allogeneic melanoma-derived cell lysate (referred to as TRIMEL) as an antigen provider and activation factor. It was recently demonstrated that TAPCell-based immunotherapy induces T-cell-mediated immune responses resulting in improved long-term survival of stage IV melanoma patients. Clinically, dendritic cell (DC) migration from injected sites to lymph nodes is an important requirement for an effective anti-tumour immunization. This mobilization of DCs is mainly driven by the C-C chemokine receptor type 7 (CCR7), which is up-regulated on mature DCs. Using flow cytometry and immunohistochemistry, we investigated if TRIMEL was capable of inducing the expression of the CCR7 on TAPCells and enhancing their migration in vitro, as well as their in vivo relocation to lymph nodes in an ectopic xenograft animal model. Our results confirmed that TRIMEL induces a phenotypic maturation and increases the expression of surface CCR7 on melanoma patient-derived DCs, and also on the monocytic/macrophage cell line THP-1. Moreover, in vitro assays showed that TRIMEL-stimulated DCs and THP-1 cells were capable of migrating specifically in the presence of the CCR7 ligand CCL19. Finally, we demonstrated that TAPCells could migrate in vivo from the injection site into the draining lymph nodes. This work contributes to an increased understanding of the biology of DCs produced ex vivo allowing the design of new strategies for effective DC-based vaccines for treating aggressive melanomas.
我们之前报道了一种生产肿瘤抗原呈递细胞(简称 TAPCells)的新方法,该方法目前正在癌症治疗中使用,使用同种异体黑素瘤来源的细胞裂解物(简称 TRIMEL)作为抗原提供物和激活因子。最近的研究表明,基于 TAPCell 的免疫疗法可诱导 T 细胞介导的免疫反应,从而提高 IV 期黑色素瘤患者的长期生存率。临床上,从注射部位向淋巴结迁移的树突状细胞(DC)是进行有效抗肿瘤免疫接种的重要要求。这种 DC 的动员主要是由 C-C 趋化因子受体 7(CCR7)驱动的,CCR7 在成熟的 DC 上上调。通过流式细胞术和免疫组织化学,我们研究了 TRIMEL 是否能够诱导 TAPCells 表达 CCR7 并增强其体外迁移能力,以及在异位异种移植动物模型中向淋巴结的体内重新定位。我们的研究结果证实,TRIMEL 诱导表型成熟并增加黑素瘤患者来源的 DC 以及单核/巨噬细胞系 THP-1 表面 CCR7 的表达。此外,体外实验表明,TRIMEL 刺激的 DC 和 THP-1 细胞能够在 CCR7 配体 CCL19 的存在下特异性迁移。最后,我们证明 TAPCells 能够从注射部位迁移到引流淋巴结。这项工作有助于更好地了解体外产生的 DC 生物学,从而为治疗侵袭性黑色素瘤的有效基于 DC 的疫苗设计提供新的策略。