Hsp70-like protein 1 fusion protein enhances induction of carcinoembryonic antigen-specific CD8+ CTL response by dendritic cell vaccine
Hsp70-like protein 1 fusion protein enhances induction of carcinoembryonic antigen-specific CD8+ CTL response by dendritic cell vaccine
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DOI：
10.1158/0008-5472.can-04-3912
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Cao, XT
中科院分区：
文献类型：
--
作者：
Wu, YF;Wan, T;Cao, XT
热休克蛋白（HSP）与抗原呈递细胞相互作用，并具有诱导抗原特异性CD8(+) CTL和Th1反应的强大佐剂能力。我们之前的工作显示了Hsp70样蛋白1 （Hsp70L1）作为Hsp70亚家族的新成员如何作为有效的Th1佐剂。在这里，我们报道了用Hsp70L1和含有CAP-1 （hla - a2限制性CTL表位）的癌胚抗原（CEA）的CEA（576-669）片段重组融合蛋白脉冲的树突状细胞有效诱导肿瘤抗原特异性免疫反应。融合蛋白CEA(576-669)-Hsp70L1能促进树突状细胞成熟，激活树突状细胞产生白细胞介素-12、白细胞介素-1 β、肿瘤坏死因子-a等细胞因子和巨噬细胞炎性蛋白-1 α、巨噬细胞炎性蛋白-1 β等趋化因子，并调节其活化、正常T的表达和分泌，表明Hsp70L1在融合蛋白中的辅助作用。CEA(576-669)-Hsp70L1脉冲树突状细胞刺激或免疫后，CEA(+)/HLA-A2.1（+）结肠癌患者或免疫后HLA-A2.1/K-b转基因小鼠脾细胞均能比单独CEA（576-669）脉冲树突状细胞更有效地产生CEA特异性HLA-A2.1限制性CD8(+) ctl，从而分泌更多的Th1细胞因子ifn - γ，并以抗原特异性和HLA-A2.1限制性方式更有效地杀伤靶细胞。CEA(576-669)- hsp70l1脉冲树突状细胞免疫的转基因小鼠脾细胞过继移植能更明显地抑制CEA*/HLA-A2.1（+）人结肠癌裸鼠的肿瘤生长和延长生存期。因此，Hsp70L1以融合蛋白的形式具有较强的佐剂作用，表明Hsp70L1可广泛用作Th1佐剂制备抗原融合蛋白，用于癌症或感染性疾病的治疗。
Heat shock proteins (HSP) have been revealed to interact with antigen-presenting cells and have potent adjuvant capability to induce antigen-specific CD8(+) CTL and Th1 responses. Our previous work shows how Hsp70-like protein 1 (Hsp70L1), as a new member of the Hsp70 subfamily, acts as potent Th1 adjuvant. Here, we report the efficient induction of tumor antigen-specific immune response by dendritic cells pulsed with recombinant fusion protein of Hsp70L1 and CEA(576-669) fragment of the carcinoembryonic antigen (CEA) containing CAP-1 (a HLA-A2-restricted CTL epitope). Fusion protein CEA(576-669)-Hsp70L1 can promote dendritic cell maturation and activate dendritic cells to produce cytokines, such as interleukin-12, interleukin-1 beta, and tumor necrosis factor-a, and chemokines, such as macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and regulated on activation, normal T expressed and secreted, indicating the adjuvant ability of Hsp70L1 in the fusion protein. CEA-specific HLA-A2.1-restricted CD8(+) CTLs either from patients with CEA(+)/HLA-A2.1(+) colon carcinoma or from splenocytes of immunized HLA-A2.1/K-b transgenic mice can be generated more efficiently after stimulations or immunizations with dendritic cells pulsed by CEA(576-669)-Hsp70L1 than with dendritic cells pulsed by CEA(576-669) alone, resulting in secreting more Th1 cytokine IFN-gamma and killing target cells more potently in an antigen-specific and HLA-A2.1-restricted manner. Adoptive transfer of splenocytes from transgenic mice immunized with CEA(576-669)-Hsp70L1-pulsed dendritic cells can inhibit tumor growth and prolong survival in nude mice bearing CEA*/HLA-A2.1(+) human colon carcinoma more markedly. Therefore, Hsp70L1 has potent adjuvant effect in form of fusion protein, indicating that Hsp70L1 may be widely used as Th1 adjuvant to prepare antigenic fusion protein for the therapeutics of cancer or infectious diseases.