Screening of cytokines to enhance vaccine effects of heat shock protein 70-rich tumor cell lysate
Screening of cytokines to enhance vaccine effects of heat shock protein 70-rich tumor cell lysate
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DOI：
10.1263/jbb.100.36
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发表时间：
2005-07-01
影响因子：
2.8
通讯作者：
Honda, H
中科院分区：
文献类型：
--
作者：
Ito, A;Fujioka, M;Honda, H
热休克蛋白（HSPs）被认为是免疫反应的重要参与者。我们以前曾报道过热处理的表达HSP 70的细胞可以介导有效的抗肿瘤免疫反应。由于成功的免疫治疗依赖于宿主的免疫系统，本研究评估了全身给予免疫细胞刺激和生长促进细胞因子是否可以增强热处理细胞裂解物疫苗（HCLV）的免疫，以进一步促进抗肿瘤免疫。在加热小鼠黑素瘤B16细胞（43 ℃，30分钟）以引起增加的HSP 70表达后，通过冻融裂解细胞以制备HCLV。在使用免疫原性差的黑色素瘤B16的方法中，与HCLV组合评估了各种细胞因子（IL-1 β、IL-2、IL-4、IL-6和IL-12、IFN-β和IFN-γ、GM-CSF和TNF-α）的作用。在第-14天和第-7天用HCLV皮下免疫同基因C57 BL/6小鼠两次，而在第-7天腹膜内注射细胞因子。在第0天进行皮下B16细胞激发。与未加热的细胞裂解物疫苗（CLV）和未接种相比，IL-12显著增强HCLV的功效。重组IL-12的全身给药增强了HCLV的功效，诱导了针对肿瘤攻击的保护性免疫，并增强了经处理小鼠中针对B16细胞的致敏脾细胞中评估的细胞毒性。这些结果表明，IL-12代表了HCLV诱导的抗肿瘤免疫应答的重要调节剂，并可能有助于进一步努力开发基于HSP 70介导的疫苗接种的新型癌症免疫疗法。
Heat shock proteins (HSPs) have been recognized as significant participants in immune reactions. We have previously reported that heat-treated cells expressing HSP70 can mediate potent antitumor immune responses. As successful immunotherapy is dependent on the host immune system, the present study evaluated whether systemic administration of immunocyte stimulatory and growth promoting cytokines could enhance heat-treated cell lysate vaccine (HCLV) immunization to further promote the antitumor immunity. After heating mouse melanoma B16 cells (43 degrees C, 30 min) to elicit increased HSP70 expression, cells were lysed by freeze thawing to prepare HCLV. In approaches using a poorly immunogenic melanoma B16, the effects of various cytokines (IL-1 beta, -2, -4, -6 and -12, IFN-beta and -gamma, GM-CSF and TNF-alpha) were assessed in combination with HCLV. Syngenic C57BL/6 mice were immunized subcutaneously with HCLV twice, on days -14 and -7, while cytokines were injected intraperitoneally on day -7. Subcutaneous B16 cell challenge was performed on day 0. IL-12 significantly enhanced the efficacy of HCLV, compared to non-heated cell lysate vaccine (CLV) and non-vaccination. Systemic administration of recombinant IL-12 augmented the efficacy of HCLV, inducing protective immunity against tumor challenge and enhancing cytotoxicity assessed in primed splenocytes against B16 cells in treated mice. These results suggest that IL-12 represents an important modulator of antitumor immune responses induced by HCLV, and may facilitate further efforts to develop novel cancer immunotherapies based on HSP70-mediated vaccination.