HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma
HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma
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DOI：
10.1002/ijc.21795
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发表时间：
2006-06-01
影响因子：
6.4
通讯作者：
Feng, ZH
中科院分区：
文献类型：
--
作者：
Geng, H;Zhang, GM;Feng, ZH
许多肿瘤免疫治疗工作集中在产生针对肿瘤抗原的强T细胞应答。然而，强烈的T细胞反应并不总是与肿瘤排斥一致，免疫抑制分子的表达上调可能是原因。在本研究中，热休克蛋白70（HSP 70）疫苗治疗诱导T细胞向肿瘤部位的浸润以及IFN-γ和IL-2的表达，并延迟肿瘤的肺转移，但最终仍发生肿瘤进展。我们证明，残留肿瘤细胞表达的B7-H1是肿瘤对HSP 70疫苗治疗产生抵抗的原因。通过静脉注射pPD-1A（编码PD-1细胞外结构域（sPD-1）的质粒）阻断B7-H1可以逆转这种耐药性并增强治疗效果。为了补充这些发现，我们通过Real-time PCR分析研究了肿瘤浸润淋巴细胞（TIL）的基因表达，结果显示，在用HSP 70疫苗联合sPD-1处理的小鼠中，TIL表达T（H）1细胞因子IFN-γ和IL-2，而负调节分子IL-10，TGF-β和foxp 3的表达降低，证明了联合治疗所提供的多功能性质可以有效地克服肿瘤抗性并促进有效的抗肿瘤免疫。用pPD-1A的体内转染可以不频繁地进行至每周一次，并且仍然产生显著的抗肿瘤效果。这些结果表明，用HSP 70疫苗治疗，然后用sPD-1阻断肿瘤-B7-H1，可能为肿瘤免疫治疗提供有希望的方法。(c)2006 Wiley-Liss，Inc.
Many tumor immunotherapy efforts are focused on the generation of strong T-cell response against tumor antigens. However, strong T-cell response does not always coincide with tumor rejection, for which upregulated expression of immunoinhibitory molecules may be responsible. In this study, the treatment with heat shock protein 70 (HSP70) vaccine induced an infiltration of T cells into the tumor site as well as the expression of IFN-gamma and IL-2, and delayed lung metastases of tumor, but the tumor progression nonetheless occur finally. We demonstrated that B7-H1 expressed by residual tumor cells was responsible for the resistance of tumor to the therapy with HSP70 vaccine. Blockade of B7-H1 by i.v. injection pPD-1A, a plasmid encoding the extracellular domain of PD-1 (sPD-1), could reverse this resistance and enhance the therapeutic efficacy. To complement these findings, we investigated the gene expression of tumor-infiltrating lymphocytes (TILs) by Real-time PCR analysis, which revealed that the expression of T(H)1 cytokines IFN-gamma and IL-2 by TIL in the mice treated with HSP70 vaccine in combination with sPD-1 was increased and the expression of negative regulatory molecules IL-10, TGF-beta and foxp3 was decreased, demonstrating that multifunctional properties afforded by the combination therapy can effectively overcome tumor resistance and promote effective antitumor immunity. The in vivo transfection with pPD-1A could be performed as infrequently as once a week and still produce a significant antitumor effect. These findings suggest that the treatment with HSP70 vaccine followed by blockade of tumor-B7-H1 with sPD-1 may provide a promising approach for tumor immunotherapy. (c) 2006 Wiley-Liss, Inc.