A Mage3/Heat Shock Protein70 DNA vaccine induces both innate and adaptive immune responses for the antitumor activity.
A Mage3/Heat Shock Protein70 DNA vaccine induces both innate and adaptive immune responses for the antitumor activity.
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DOI：
10.1016/j.vaccine.2009.09.119
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发表时间：
2009-12-11
期刊：
影响因子：
5.5
通讯作者：
Huang XF
中科院分区：
文献类型：
--
作者：
Wang L;Rollins L;Gu Q;Chen SY;Huang XF
热休克蛋白(HSPs)是一种高效、多功能的抗肿瘤免疫分子。我们测试了基于HSP的DNA疫苗是否能够诱导对Mage3的有效免疫应答，Mage3是一种在许多人类肿瘤中频繁表达的癌症睾丸(CT)抗原，从而控制了Mage3表达的肿瘤。该疫苗是通过将人可诱导的HSP70连接到修饰的Mage3基因(SMage3)的C端而构建的，该基因的N端与人RANTES的信号前导序列相连，用于从转导细胞中释放表达的融合蛋白。肌肉注射sMage3HspDNA可诱导小鼠产生CD4+/CD8+T细胞和抗体。SMage3HspDNA疫苗对表达Mage3的TC-1肿瘤有更强的抑制作用。当我们用sMage3HspDNA免疫CD4+和CD8+基因敲除小鼠后，我们解剖了CD8+和CD8+T细胞的抗肿瘤活性，发现CD8+T细胞和CD8+T细胞在预防性免疫中都起到了控制肿瘤的作用，但并不构成免疫保护的整体。相反，自然杀伤(NK)细胞的耗尽导致免疫小鼠的抗肿瘤活性严重丧失。这些结果表明，基于HSP的Mage3 DNA疫苗可以通过HSP相关的佐剂功能诱导先天免疫反应和Mage3特异性获得性免疫反应，从而更有效地抑制肿瘤生长。
Heat shock proteins (HSPs) are highly effective and versatile molecules in promoting anti-tumor immune responses. We tested whether a HSP-based DNA vaccine can induce effective immune response against Mage3, a cancer testis (CT) antigen frequently expressed in many human tumors, thereby controlling the Mage3-expressing tumor. The vaccine was constructed by linking human inducible HSP70 to the C-terminus of a modified Mage3 gene (sMage3) that was attached at its N-terminus with the signal leader sequence of the human RANTES for releasing the expressed fusion protein from the transduced cells. Intramuscular injection of sMage3Hsp DNA induced CD4+/CD8+ T cell and antibody responses. Vaccination with sMage3Hsp DNA was more effective in inhibiting Mage3-expressing TC-1 tumors. When we dissected the antitumor activity of CD4+ and CD8+ T cells by immunizing CD4+ and CD8+ knockout mice with sMage3Hsp DNA, we found that both CD8+ T and CD4+ T cells played a role in control of inoculated tumor, but did not constitute the whole of immune protection in the prophylactic immunization. Instead, depletion of natural killer (NK) cells led to a major loss of anti-tumor activity in the immunized mice. These results indicate that the HSP-based Mage3 DNA vaccine can more effectively inhibit tumor growth by inducing both the innate immune responses and Mage3-specific adaptive immune responses via the Hsp-associated adjuvant function.
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