Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH Building 29B, Room 2NN20, 29 Lincoln Drive MSC 4555, Bethesda, MD 20892, USA.
J Transl Med. 2010 Nov 10;8:116. doi: 10.1186/1479-5876-8-116.
DNA vaccines represent an attractive approach for cancer treatment by inducing active T cell and B cell immune responses to tumor antigens. Previous studies have shown that interleukin-13 receptor α2 chain (IL-13Rα2), a tumor-associated antigen is a promising target for cancer immunotherapy as high levels of IL-13Rα2 are expressed on a variety of human tumors. To enhance the effectiveness of DNA vaccine, we used extracellular domain of IL-13Rα2 (ECDα2) as a protein-boost against murine tumor models.
We have developed murine models of tumors naturally expressing IL-13Rα2 (MCA304 sarcoma, 4T1 breast carcinoma) and D5 melanoma tumors transfected with human IL-13Rα2 in syngeneic mice and examined the antitumor activity of DNA vaccine expressing IL-13Rα2 gene with or without ECDα2 protein mixed with CpG and IFA adjuvants as a boost vaccine.
Mice receiving IL-13Rα2 DNA vaccine boosted with ECDα2 protein were superior in exhibiting inhibition of tumor growth, compared to mice receiving DNA vaccine alone, in both prophylactic and therapeutic vaccine settings. In addition, prime-boost vaccination significantly prolonged the survival of mice compared to DNA vaccine alone. Furthermore, ECDα2 booster vaccination increased IFN-γ production and CTL activity against tumor expressing IL-13Rα2. The immunohistochemical analysis showed the infiltration of CD4 and CD8 positive T cells and IFN-γ-induced chemokines (CXCL9 and CXCL10) in regressing tumors of immunized mice. Finally, the prime boost strategy was able to reduce immunosuppressive CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in the spleen and tumor of vaccinated mice.
These results suggest that immunization with IL-13Rα2 DNA vaccine followed by ECDα2 boost mixed with CpG and IFA adjuvants inhibits tumor growth in T cell dependent manner. Thus our results show an enhancement of efficacy of IL-13Rα2 DNA vaccine with ECDα2 protein boost and offers an exciting approach in the development of new DNA vaccine targeting IL-13Rα2 for cancer immunotherapy.
DNA 疫苗通过诱导针对肿瘤抗原的主动 T 细胞和 B 细胞免疫反应，代表了癌症治疗的一种有吸引力的方法。先前的研究表明，白细胞介素 13 受体 α2 链（IL-13Rα2）作为一种肿瘤相关抗原，是癌症免疫治疗的一个有前途的靶点，因为多种人类肿瘤高表达 IL-13Rα2。为了提高 DNA 疫苗的有效性，我们使用了 IL-13Rα2 的细胞外结构域（ECDα2）作为一种蛋白质增强剂，用于针对鼠肿瘤模型。
我们在同基因小鼠中建立了自然表达 IL-13Rα2 的肿瘤模型（MCA304 肉瘤、4T1 乳腺癌）和转染人 IL-13Rα2 的 D5 黑色素瘤肿瘤模型，并检查了表达 IL-13Rα2 基因的 DNA 疫苗与 ECDα2 蛋白混合 CpG 和 IFA 佐剂作为增强疫苗的抗肿瘤活性。
与单独接受 DNA 疫苗的小鼠相比，接受 ECDα2 蛋白增强的 IL-13Rα2 DNA 疫苗的小鼠在预防和治疗疫苗设置中均能更好地抑制肿瘤生长。此外，与单独接受 DNA 疫苗相比，初免-加强疫苗接种显著延长了小鼠的存活时间。此外，ECDα2 增强疫苗接种增加了针对表达 IL-13Rα2 的肿瘤的 IFN-γ 产生和 CTL 活性。免疫组织化学分析显示，在免疫接种小鼠的消退肿瘤中浸润了 CD4 和 CD8 阳性 T 细胞和 IFN-γ 诱导的趋化因子（CXCL9 和 CXCL10）。最后，初免-加强策略能够减少接种小鼠脾脏和肿瘤中的免疫抑制性 CD4+CD25+Foxp3+调节性 T 细胞（Tregs）。
这些结果表明，IL-13Rα2 DNA 疫苗接种后用 ECDα2 增强混合 CpG 和 IFA 佐剂可以依赖 T 细胞抑制肿瘤生长。因此，我们的结果表明，用 ECDα2 蛋白增强 IL-13Rα2 DNA 疫苗可提高其疗效，并为开发针对 IL-13Rα2 的新型 DNA 疫苗提供了一种令人兴奋的癌症免疫治疗方法。
