Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70
Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70
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DOI：
10.1002/ijc.28858
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发表时间：
2014-11-01
影响因子：
6.4
通讯作者：
Margulis, Boris A.
中科院分区：
文献类型：
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作者：
Shevtsov, Maxim A.;Pozdnyakov, Alexander V.;Margulis, Boris A.
分子伴侣Hsp 70可激活获得性免疫，提示其可能用作抗肿瘤疫苗。为了评估Hsp 70的治疗能力，我们将纯化的伴侣蛋白施用到C6胶质母细胞瘤脑肿瘤中，并探索了治疗动物中淋巴细胞的活力和肿瘤大小以及干扰素γ（IFN γ）产生和细胞毒性。靶向瘤内注射Hsp 70导致其在胶质母细胞瘤区域内的分布，并引起肿瘤进展的显著抑制，如通过磁共振成像所证实的。肿瘤生长的延迟对应于荷瘤动物长达31天的延长生存期，而对照组为20天。用渗透泵连续给予Hsp 70甚至进一步增加存活（39天）。治疗效果与NK细胞（Ly-6c+）和T淋巴细胞（CD 3+、CD 4+和CD 8+）向胶质母细胞瘤的浸润以及NK细胞（颗粒酶B产生）和CD 81 T淋巴细胞活性的增加相关，如IFN γ ELISPOT测定所示。此外，我们发现，热休克蛋白70治疗导致伴随着10倍的IFN γ产生，增加抗C6肿瘤细胞毒性的淋巴细胞。总之，肿瘤内持续递送Hsp 70显示出高治疗潜力，因此可应用于胶质母细胞瘤的治疗。
Chaperone Hsp70 can activate adaptive immunity suggesting its possible application as an antitumor vaccine. To assess the therapeutic capacity of Hsp70 we administered purified chaperone into a C6 glioblastoma brain tumor and explored the viability and tumor size as well as interferon gamma (IFN gamma) production and cytotoxicity of lymphocytes in the treated animals. Targeted intratumoral injection of Hsp70 resulted in its distribution within the area of glioblastoma, and caused significant inhibition of tumor progression as confirmed by magnetic resonance imaging. The delay in tumor growth corresponded to the prolonged survival of tumor-bearing animals of up to 31 days versus 20 days in control. Continuous administration of Hsp70 with an osmotic pump increased survival even further (39 days). Therapeutic efficacy was associated with infiltration to glioblastoma of NK cells (Ly-6c+) and T lymphocytes (CD3+, CD4+ and CD8+) as well as with an increase in the activity of NK cells (granzyme B production) and CD81 T lymphocytes as shown by IFN gamma ELISPOT assay. Furthermore, we found that Hsp70 treatment caused concomitantly, with a tenfold elevated IFN gamma production, an increase in anti-C6 tumor cytotoxicity of lymphocytes. In conclusion, continuous intratumoral delivery of Hsp70 demonstrates high therapeutic potential and therefore could be applied in the treatment of glioblastoma.