Regression of intestinal adenomas by vaccination with heat shock protein 105-pulsed bone marrow-derived dendritic cells in ApcMin/+ mice
Regression of intestinal adenomas by vaccination with heat shock protein 105-pulsed bone marrow-derived dendritic cells in ApcMin/+ mice
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DOI：
10.1111/j.1349-7006.2007.00612.x
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发表时间：
2007-12-01
期刊：
影响因子：
5.7
通讯作者：
Nishimura, Yasuharu
中科院分区：
文献类型：
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作者：
Yokomine, Kazunori;Nakatsura, Tetsuya;Nishimura, Yasuharu
热休克蛋白（HSP）105在多种癌症中过表达，但在许多正常组织中表达水平较低，睾丸除外。用HSP 105脉冲的骨髓来源的树突状细胞（BM-DC）接种疫苗在小鼠模型中诱导抗肿瘤免疫而不引起自身免疫反应。因为Apc（Min/+）小鼠在4月龄时在整个肠道中发展出多个腺瘤，所以小鼠提供了临床相关的人肠道肿瘤模型。在本研究中，我们研究了HSP 105脉冲的BM-DC疫苗对Apc（Min/+）小鼠中肿瘤消退的功效。Western blot和免疫组化分析显示Apc（Min/+）小鼠肿瘤内源性过表达HSP 105。在6、8和10周龄时用HSP 105脉冲的BM-DC疫苗免疫Apc（Min/+）小鼠显著减少了小肠息肉的数量，伴随着肿瘤中CD 4（+）和CD 8（+）T细胞的浸润。细胞耗竭实验证明，CD 4（+）和CD 8（+）T细胞在这些疫苗诱导的抗肿瘤免疫激活中起关键作用。这些发现表明，HSP 105脉冲的BM-DC疫苗可以为由于肿瘤抑制基因失活而自发出现的肿瘤提供有效的免疫治疗，例如在Apc（Min/+）小鼠模型中。
Heat shock protein (HSP) 105 is overexpressed in various cancers, but is expressed at low levels in many normal tissues, except for the testis. A vaccination with HSP105-pulsed bone marrow-derived dendritic cells (BM-DC) induced antitumor immunity without causing an autoimmune reaction in a mouse model. Because Apc(Min/+) mice develop multiple adenomas throughout the intestinal tract by 4 months of age, the mice provide a clinically relevant model of human intestinal tumor. In the present study, we investigated the efficacy of the HSP105-pulsed BM-DC vaccine on tumor regression in the Apc(Min/+) mouse. Western blot and immunohistochemical analyses revealed that the tumors of the Apc(Min/+) mice endogenously overexpressed HSP105. Immunization of the Apc(Min/+) mice with a HSP105-pulsed BM-DC vaccine at 6, 8, and 10 weeks of age significantly reduced the number of small-intestinal polyps accompanied by infiltration of both CD4(+) and CD8(+) T cells in the tumors. Cell depletion experiments proved that both CD4(+) and CD8(+) T cells play a critical role in the activation of antitumor immunity induced by these vaccinations. These findings indicate that the HSP105-pulsed BM-DC vaccine can provide potent immunotherapy for tumors that appear spontaneously as a result of the inactivation of a tumor suppressor gene, such as in the Apc(Min/+) mouse model.