Hu Jinwei, Yuan Xiangpeng, Belladonna Maria L, Ong John M, Wachsmann-Hogiu Sebastian, Farkas Daniel L, Black Keith L, Yu John S
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Cancer Res. 2006 Sep 1;66(17):8887-96. doi: 10.1158/0008-5472.CAN-05-3448.
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.
树突状细胞（DCs）是强大的抗原呈递细胞，在启动针对肿瘤的免疫反应中起关键作用。白细胞介素（IL）-23可直接作用于DC，在体外促进肿瘤肽的免疫原性呈递。在此，我们在小鼠颅内胶质瘤模型中评估了骨髓来源的DC与IL-23联合使用对诱导抗肿瘤免疫的作用。DC可被编码单链小鼠IL-23的腺病毒载体转导，以表达高水平的生物活性IL-23。瘤内植入表达IL-23的DC对颅内荷瘤小鼠产生了保护作用。这些小鼠因此获得了针对相同肿瘤再次攻击的全身免疫力。表达IL-23的DC的保护作用与表达IL-12的DC相当，甚至更好。IL-23转导的DC（DC-IL-23）治疗导致瘤内CD8(+)和CD4(+) T细胞大量浸润，并在区域淋巴结和脾脏中诱导对肿瘤的特异性TH1型反应，其水平高于未转导的DC。此外，用DC-IL-23治疗的动物的脾细胞显示出更高水平的特异性CTL活性。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CD8(+) T细胞，CD4(+) T细胞和自然杀伤细胞也参与其中。总之，瘤内注射DC-IL-23在颅内荷瘤小鼠中产生了显著且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强大肿瘤特异性免疫的新方法。这种方法可能对治疗人类胶质瘤具有治疗潜力。
