Department of Oncology, Changhai Hospital of Shanghai, China.
Cell Mol Immunol. 2011 Sep;8(5):424-32. doi: 10.1038/cmi.2011.21. Epub 2011 Jul 25.
Heat shock proteins (HSPs) have been shown to interact with antigen-presenting cells (APCs), especially dendritic cells (DCs). HSPs act as potent adjuvants, inducing a Th1 response, as well as antigen-specific CD8(+) cytotoxic T lymphocytes (CTL) via cross-presentation. Our previous work has demonstrated that Hsp70-like protein 1 (Hsp70L1), a new member of the Hsp70 subfamily, can act as a powerful Th1 adjuvant in a DC-based vaccine. Here we report the efficient induction of tumor antigen-specific T cell immune response by DCs pulsed with recombinant fusion protein of Hsp70L1 and Her2(341-456), the latter of which is a fragment of Her2/neu (Her2) containing E75 (a HLA-A2 restricted CTL epitope). The fusion protein Hsp70L1-Her2(341-456) promotes the maturation of DCs and activates them to produce cytokines, such as IL-12 and TNF-α, and chemokines, such as MIP-1α, MIP-1β and RANTES. Taken together, these results indicate that the adjuvant activity of Hsp70L1 is maintained in the fusion protein. Her2-specific HLA-A2.1-restricted CD8(+) CTLs can be generated efficiently either from the Peripheral blood lymphocytes (PBL) of healthy donors or from the splenocytes of immunized HLA-A2.1/K(b) transgenic mice by in vitro stimulation or immunization with DCs pulsed with the Hsp70L1-Her2(341-456) fusion protein. This results in more potent target cell killing in an antigen-specific and HLA-A2.1-restricted manner. Adoptive transfer of splenocytes from transgenic mice immunized with Hsp70L1-Her2(341-456)-pulsed DCs can markedly inhibit tumor growth and prolong the survival of nude mice with Her2(+)/HLA-A2.1(+) human carcinomas. These results suggest that Hsp70L1-Her2(341-456)-pulsed DCs could be a new therapeutic vaccine for patients with Her2(+) cancer.
热休克蛋白（HSPs）已被证明与抗原呈递细胞（APCs）相互作用，特别是树突状细胞（DCs）。HSPs 作为有效的佐剂，通过交叉呈递诱导 Th1 反应以及抗原特异性 CD8+细胞毒性 T 淋巴细胞（CTL）。我们之前的工作表明，热休克蛋白 70 样蛋白 1（Hsp70L1），热休克蛋白 70 亚家族的新成员，可以在基于 DC 的疫苗中作为强大的 Th1 佐剂。在这里，我们报告了通过用重组融合蛋白 Hsp70L1 和 Her2（341-456）脉冲的 DC 有效诱导肿瘤抗原特异性 T 细胞免疫应答，后者是 Her2/neu（Her2）的一个片段，包含 E75（一个 HLA-A2 限制的 CTL 表位）。融合蛋白 Hsp70L1-Her2（341-456）促进 DC 的成熟，并激活它们产生细胞因子，如 IL-12 和 TNF-α，以及趋化因子，如 MIP-1α、MIP-1β 和 RANTES。总之，这些结果表明 Hsp70L1 的佐剂活性在融合蛋白中得以维持。可以从健康供体的外周血淋巴细胞（PBL）或免疫 HLA-A2.1/K（b）转基因小鼠的脾细胞中有效地产生针对 Her2 的 HLA-A2.1 限制性 CD8+CTL，通过体外刺激或用 Hsp70L1-Her2（341-456）融合蛋白脉冲的 DC 进行免疫。这导致以抗原特异性和 HLA-A2.1 限制的方式更有效地杀伤靶细胞。用 Hsp70L1-Her2（341-456）-脉冲 DC 免疫的转基因小鼠脾细胞的过继转移可以显著抑制 Her2（+）/HLA-A2.1（+）人癌裸鼠的肿瘤生长并延长其存活时间。这些结果表明，Hsp70L1-Her2（341-456）-脉冲 DC 可能是 Her2（+）癌症患者的一种新的治疗性疫苗。
