Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors.
Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors.
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DOI：
10.1182/blood.v96.1.91
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发表时间：
2000-07
期刊：
影响因子：
20.3
通讯作者：
Toshiaki Kikuchi;Malcolm A. S. Moore;Ronald G. Crystal
中科院分区：
文献类型：
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作者：
Toshiaki Kikuchi;Malcolm A. S. Moore;Ronald G. Crystal
CD40配体(CD40L)是启动抗原特异性T细胞反应的关键分子。本研究基于一种假设，即体外修饰表达CD40L的树突状细胞(DCs)将增强体内肿瘤抗原向细胞免疫系统的递呈，从而诱导抗肿瘤免疫以抑制肿瘤生长。为了验证这一概念，将表达小鼠CD40L(AdmCD40L)的重组腺病毒(AdmCD40L)体外修饰的骨髓来源DC注射到小鼠皮下肿瘤中。在B16(H-2(B)，黑色素瘤)和CT26(H-2(D)，结肠癌)小鼠模型中，瘤内注射2×10(6)AdmCD40L修饰的DC(CD40L-DC)对已建立的(第8天)皮下肿瘤导致持续的肿瘤消退和生存优势。当CD40L-DC的数量减少10倍至2×10(5)时，这种抗肿瘤作用持续存在。对CD40L-DC处理动物的脾分析表明，注射到CT26侧翼肿瘤皮下的CD40L-DC迁移到脾，导致免疫相关过程的激活。与这一概念一致，CD40L-DC瘤内给药可诱导肿瘤特异性细胞毒性T淋巴细胞反应，而CD40L-DC治疗小鼠的脾细胞转移有效地保护幼小鼠免受随后的肿瘤攻击。在远处转移疾病的2个肿瘤模型中，右侧未经治疗的B16肿瘤与直接注射CD40L-DC治疗的左侧B16肿瘤平行消退。这些结果支持这样一个概念，即用重组CD40L腺病毒载体对DC进行基因修饰可能是一种有用的策略，可以直接激活DC用于癌症免疫治疗。
CD40 ligand (CD40L) is essential for the initiation of antigen-specific T-cell responses. This study is based on the hypothesis that dendritic cells (DCs) genetically modified ex vivo to express CD40L will enhance in vivo presentation of tumor antigen to the cellular immune system with consequent induction of antitumor immunity to suppress tumor growth. To examine this concept, subcutaneous murine tumors were injected with bone marrow-derived DCs that had been modified in vitro with an adenovirus (Ad) vector expressing murine CD40L (AdmCD40L). In B16 (H-2(b), melanoma) and CT26 (H-2(d), colon cancer) murine models, intratumoral injection of 2 x 10(6) AdmCD40L-modified DCs (CD40L-DCs) to established (day 8) subcutaneous tumors resulted in sustained tumor regression and survival advantage. This antitumor effect was sustained when the number of CD40L-DCs were reduced 10-fold to 2 x 10(5). Analysis of spleens from CD40L-DC-treated animals demonstrated that CD40L-DCs injected into the subcutaneous CT26 flank tumors migrated to the spleen, resulting in activation of immune-relevant processes. Consistent with this concept, intratumoral administration of CD40L-DCs elicited tumor-specific cytotoxic T-lymphocyte responses, and the transfer of spleen cells from CD40L-DC-treated mice efficiently protected naive mice against a subsequent tumor challenge. In a distant 2-tumor model of metastatic disease, an untreated B16 tumor in the right flank regressed in parallel with a left B16 tumor treated with direct injection of CD40L-DCs. These results support the concept that genetic modification of DCs with a recombinant CD40L adenovirus vector may be a useful strategy for directly activating DCs for cancer immunotherapy.