Potent tumor-specific immunity induced by an in vivo heat shock protein-suicide gene-based tumor vaccine
Potent tumor-specific immunity induced by an in vivo heat shock protein-suicide gene-based tumor vaccine
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DOI：
10.1158/0008-5472.can-04-1084
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Huang, XF
中科院分区：
文献类型：
--
作者：
Ren, WH;Strube, R;Huang, XF
肿瘤细胞具有独特的突变抗原和共有的自身抗原的库，但通常不能激发有效的免疫应答，这可能是因为专职抗原呈递细胞的抗原呈递不足。热休克蛋白（Heat shock proteins，HSPs）是一种重要的内源性危险信号分子，通过与抗原呈递肽分子形成伴侣，在天然免疫和获得性免疫中发挥重要作用。虽然在小鼠和一些临床试验中有效地诱导肿瘤特异性免疫，但肿瘤来源的HSP与疫苗一样具有许多局限性，例如从个体患者切除的肿瘤中离体制备足够量的HSP的技术困难。在这里，我们已经开发了一种在体内HSP自杀基因肿瘤疫苗，通过产生的重组复制缺陷型腺病毒（Ad-HT），共表达HSP 70和疱疹。单纯病毒胸苷激酶自杀基因。HSP70过表达原位和胸苷激酶/更昔洛韦治疗的肿瘤杀伤相结合，但无论是单独的策略，激发有效的全身抗肿瘤活性后，瘤内注射的Ad-HT。瘤内注射Ad-HT可诱导肿瘤特异性CD4（+）和CD8（+）T细胞应答。从用Ad-HT处理的小鼠中分离的CD11c（+）树突状细胞（DC）能够引发肿瘤特异性CTL。总的来说，这些结果表明，通过激活自杀基因释放肿瘤抗原的肿瘤杀伤和原位HSP 70过表达增强DC抗原呈递的组合克服了宿主对肿瘤抗原的免疫耐受，导致诱导有效的抗肿瘤免疫。我们的研究结果可能具有广泛的相关性，在体内HSP/自杀基因肿瘤疫苗在治疗人类实体瘤。
Tumor cells harbor a repertoire of unique, mutated antigens and shared self-antigens but generally are incapable of provoking an effective immune response, likely because of inadequate antigen presentation by professional antigen-presenting cells. Heat shock proteins (HSPs) play important roles in eliciting innate and adaptive immunity by chaperoning peptides for antigen presentation and providing endogenous danger signaling. Although effective in inducing tumor-specific immunity in mice and in some clinical trials, tumor-derived HSPs have many limitations like vaccines, such as the technical difficulty of ex vivo preparation of adequate quantities of HSPs from the resected tumors of individual patients. Here we have developed an in vivo HSP-suicide gene tumor vaccine by generating a recombinant replication-defective adenovirus (Ad-HT) that coexpresses HSP70 and a herpes. simplex virus thymidine kinase suicide gene. The combination of HSP70 overexpression in situ and tumor killing by thymidine kinase/ganciclovir treatment, but neither strategy alone, provoked potent systemic antitumor activities after intratumor injection of Ad-HT. Tumor-specific CD4(+) and CD8(+) T-cell responses were induced by Ad-HT intratumor injection. CD11c(+) dendritic cells (DCs) isolated from mice treated with Ad-HT were able to prime tumor-specific CTLs. Collectively, these results indicate that the combination of tumor killing by activation of a suicide gene to release tumor antigens and in situ HSP70 overexpression to enhance DC antigen presentation overcomes host immune tolerance to tumor antigens, leading to the induction of potent antitumor immunity. Our findings may have broad relevance to the use of the in vivo HSP/suicide gene tumor vaccine in therapy for human solid tumors.