体外将整个淋巴瘤细胞特异性靶向树突状细胞可提供一种有效的抗肿瘤疫苗。

Specific targeting of whole lymphoma cells to dendritic cells ex vivo provides a potent antitumor vaccine.

作者信息

Adam Christian, Mysliwietz Josef, Mocikat Ralph

机构信息

GSF-Institut für Molekulare Immunologie, Marchioninistr, 25, 81377 München, Germany.

出版信息

J Transl Med. 2007 Mar 14;5:16. doi: 10.1186/1479-5876-5-16.

BACKGROUND

Dendritic cells (DC) pulsed with tumor-derived antigenic material have widely been used in antitumor vaccination protocols. However, the optimal strategy of DC loading has not yet been established. Our aim was to define requirements of optimal DC vaccines in terms of in vivo protection in a murine B-cell lymphoma model.

METHODS

We compare various loading reagents including whole parental and modified tumor cells and a single tumor-specific antigen, namely the lymphoma idiotype (Id). Bone marrow-derived DC were pulsed in vitro and used for therapy of established A20 lymphomas.

RESULTS

We show that a vaccine with superior antitumor efficacy can be generated when DC are loaded with whole modified tumor cells which provide both (i) antigenic polyvalency and (ii) receptor-mediated antigen internalization. Uptake of cellular material was greatly enhanced when the tumor cells used for DC pulsing were engineered to express an anti-Fc receptor immunoglobulin specificity. Upon transfer of these DC, established tumor burdens were eradicated in 50% of mice. By contrast, pulsing DC with unmodified lymphoma cells or with the lymphoma Id, even when it was endowed with the anti-Fc receptor binding arm, was far less effective. A specific humoral anti-Id response could be detected, particularly following delivery of Id protein-pulsed DC, but it was not predictive of tumor protection. Instead a T-cell response was pivotal for successful tumor protection. Interaction of the transferred DC with CD8+ T lymphocytes seemed to play a role for induction of the immune response but was dispensable when DC had received an additional maturation stimulus.

CONCLUSION

Our analyses show that the advantages of specific antigen redirection and antigenic polyvalency can be combined to generate DC-based vaccines with superior antitumor efficacy. This mouse model may provide information for the standardization of DC-based vaccination protocols.

背景

用肿瘤衍生抗原物质脉冲处理的树突状细胞（DC）已广泛应用于抗肿瘤疫苗接种方案。然而，DC负载的最佳策略尚未确立。我们的目的是在小鼠B细胞淋巴瘤模型的体内保护方面确定最佳DC疫苗的要求。

方法

我们比较了各种负载试剂，包括完整的亲本肿瘤细胞和修饰的肿瘤细胞以及单一的肿瘤特异性抗原，即淋巴瘤独特型（Id）。体外脉冲处理骨髓来源的DC，并用于治疗已建立的A20淋巴瘤。

结果

我们发现，当DC用完整的修饰肿瘤细胞负载时，可以产生具有卓越抗肿瘤功效的疫苗，这些肿瘤细胞既提供（i）抗原多价性，又提供（ii）受体介导的抗原内化。当用于DC脉冲处理的肿瘤细胞被设计表达抗Fc受体免疫球蛋白特异性时，细胞物质的摄取大大增强。转移这些DC后，50%的小鼠体内已建立的肿瘤负荷被根除。相比之下，用未修饰的淋巴瘤细胞或淋巴瘤Id脉冲处理DC，即使赋予其抗Fc受体结合臂，效果也差得多。可以检测到特异性体液抗Id反应，特别是在递送Id蛋白脉冲处理的DC后，但它不能预测肿瘤保护作用。相反，T细胞反应对于成功的肿瘤保护至关重要。转移的DC与CD8+T淋巴细胞的相互作用似乎在免疫反应的诱导中起作用，但当DC接受额外的成熟刺激时则不是必需的。