Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells
Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells
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DOI：
10.1158/0008-5472.can-05-3448
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Yu, John S.
中科院分区：
文献类型：
--
作者：
Hu, Jinwei;Yuan, Xiangpeng;Yu, John S.
树突状细胞（Dendritic cells，DC）是一种强有力的抗原提呈细胞，在启动肿瘤免疫应答中起着关键作用。白细胞介素（IL）-23在体外可直接作用于DC，促进肿瘤肽的免疫原性提呈。在这里，我们评估了骨髓来源的DC和IL-23的组合在小鼠颅内胶质瘤模型中诱导抗肿瘤免疫。DC可以通过编码单链小鼠IL-23的腺病毒载体转导以表达高水平的生物活性IL-23。肿瘤内植入表达IL-23的DC对颅内荷瘤小鼠产生保护作用。小鼠因此获得了针对相同肿瘤再激发的全身免疫力。表达IL-23的DC的保护作用与表达IL-12的DC相当或甚至更好。IL-23转导的DC（DC-IL-23）治疗导致了强烈的肿瘤内CD 8（+）和CD 4（+）T细胞浸润，并诱导了对局部淋巴结和脾脏中肿瘤的特异性TH 1型应答，其水平高于未转导的DC。此外，来自用DC-IL-23处理的动物的脾细胞显示出升高的特异性CTL活性水平。体内淋巴细胞清除实验表明DC-IL-23诱导的抗肿瘤免疫主要依赖于CD 8（+）T细胞，CD 4（+）T细胞和自然杀伤细胞也参与其中。总之，i. t.注射DC-IL-23在携带颅内肿瘤的小鼠中产生显著和有效的全身抗肿瘤免疫。这些发现提示了一种诱导针对颅内肿瘤的有效肿瘤特异性免疫的新方法。这种方法可能具有治疗人类胶质瘤的潜力。
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming immune responses to tumor. Interleukin (IL)-23 can act directly on DC to promote immunogenic presentation of tumor peptide in vitro. Here, we evaluated the combination of bone marrow-derived DC and IL-23 on the induction of antitumor immunity in a mouse intracranial glioma model. DCs can be transduced by an adenoviral vector coding single-chain mouse IL-23 to express high levels of bioactive IL-23. Intratumoral implantation of IL-23-expressing DCs produced a protective effect on intracranial tumor-bearing mice. The mice consequently gained systemic immunity against the same tumor rechallenge. The protective effect of IL-23-expressing DCs was comparable with or even better than that of IL-12-expressing DCs. IL-23-transduced DC (DC-IL-23) treatment resulted in robust intratumoral CD8(+) and CD4(+) T-cell infiltration and induced a specific TH1-type response to the tumor in regional lymph nodes and spleen at levels greater than those of nontransduced DCs. Moreover, splenocytes from animals treated with DC-IL-23 showed heightened levels of specific CTL activity. In vivo lymphocyte depletion experiments showed that the antitumor immunity induced by DC-IL-23 was mainly dependent on CD8(+) T cells and that CD4(+) T cells and natural killer cells were also involved. In summary, i.t. injection of DC-IL-23 resulted in significant and effective systemic antitumor immunity in intracranial tumor-bearing mice. These findings suggest a new approach to induce potent tumor-specific immunity to intracranial tumors. This approach may have therapeutic potential for treating human glioma.