Interleukin-13 receptor α2 DNA prime boost vaccine induces tumor immunity in murine tumor models.
Interleukin-13 receptor α2 DNA prime boost vaccine induces tumor immunity in murine tumor models.
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DOI：
10.1186/1479-5876-8-116
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发表时间：
2010-11-10
影响因子：
7.4
通讯作者：
Puri RK
中科院分区：
文献类型：
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作者：
Nakashima H;Fujisawa T;Husain SR;Puri RK
DNA疫苗通过诱导针对肿瘤抗原的活性T细胞和B细胞免疫应答而代表用于癌症治疗的有吸引力的方法。肿瘤相关抗原白细胞介素13受体α2链（IL-13 R α2）在多种人类肿瘤中高水平表达，是肿瘤免疫治疗的一个有前景的靶点。为了增强DNA疫苗的有效性，我们使用IL-13 R α2的胞外结构域（ECDα2）作为针对小鼠肿瘤模型的蛋白加强免疫。我们在同基因小鼠中建立了天然表达IL-13 R α2的肿瘤（MCA 304肉瘤，4 T1乳腺癌）和转染人IL-13 R α2的D5黑素瘤肿瘤的小鼠模型，并检测了表达IL-13 R α2基因的DNA疫苗与CpG和IFA佐剂混合作为加强疫苗的抗肿瘤活性。在预防性和治疗性疫苗设置中，与单独接受DNA疫苗的小鼠相比，接受用ECDα2蛋白加强的IL-13 R α2 DNA疫苗的小鼠在显示肿瘤生长抑制方面具有上级优势。此外，与单独的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加强疫苗接种增加了IFN-γ产生和针对表达IL-13 R α2的肿瘤的CTL活性。免疫组化显示免疫小鼠肿瘤消退过程中有CD 4和CD 8阳性T细胞浸润，并有IFN-γ诱导的趋化因子（CXCL 9和CXCL 10）表达。最后，初免加强免疫策略能够减少免疫接种小鼠的脾脏和肿瘤中的免疫抑制性CD 4 + CD 25 + Foxp 3+调节性T细胞（TcB）。这些结果表明，IL-13 R α2 DNA疫苗免疫后，ECDα2与CpG和IFA佐剂混合的加强免疫以T细胞依赖的方式抑制肿瘤生长。因此，我们的研究结果表明，ECDα2蛋白加强IL-13 R α2 DNA疫苗的效力增强，并为开发新的靶向IL-13 R α2的DNA疫苗用于癌症免疫治疗提供了令人兴奋的方法。
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.