DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4+ T cells and CD8+ T cells
DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4+ T cells and CD8+ T cells
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DOI：
10.1111/j.1349-7006.2005.00093.x
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发表时间：
2005-10-01
期刊：
影响因子：
5.7
通讯作者：
Nishimura, Y
中科院分区：
文献类型：
--
作者：
Miyazaki, M;Nakatsura, T;Nishimura, Y
我们报告说，HSP 105，通过重组表达克隆（SEREX）抗原的血清学鉴定，是过度表达在各种人类癌症，包括结直肠癌，胰腺癌，甲状腺癌，食管癌，乳腺癌，但不表达在正常组织中，除了睾丸。HSP 105的氨基酸序列和表达模式在人类和小鼠中非常相似。在这项研究中，我们建立了一个临床前研究，以探讨DNA疫苗生产小鼠HSP 105全蛋白的肿瘤免疫治疗在体内使用BALB/c和C57 BL/6小鼠，Colon 26，同源内源性表达HSP 105的结直肠癌细胞系，B16.F10，黑色素瘤细胞系。DNA疫苗用于刺激HSP 105特异性T细胞应答。用HSP 105 DNA疫苗免疫的小鼠中有50%完全抑制皮下Colon 26或B16.F10细胞的生长，伴随着CD 4（+）T细胞和CD 8（+）T细胞向肿瘤中的大量浸润。在细胞转移或耗竭实验中，我们证明了由这些疫苗诱导的CD 4（+）T细胞和CD 8（+）T细胞在抗肿瘤免疫的激活中起关键作用。在拒绝肿瘤细胞攻击的存活小鼠中不存在自身免疫反应的证据。我们发现HSP 105在小鼠中具有高度免疫原性，并且HSP 105 DNA疫苗接种诱导抗肿瘤免疫而不引起自身免疫。因此，HSP 105是一种理想的肿瘤抗原，可用于免疫治疗或预防各种过表达HSP 105的人类肿瘤，包括结直肠癌和黑色素瘤。
We report that HSP105, identified by serological identification of antigens by recombinant expression cloning (SEREX), is over-expressed in a variety of human cancers, including colorectal, pancreatic, thyroid, esophageal, and breast carcinoma, but is not expressed in normal tissues except for the testis. The amino acid sequences and expression patterns of HSP105 are very similar in humans and mice. In this study, we set up a preclinical study to investigate the usefulness of a DNA vaccine producing mouse HSP105 whole protein for cancer immunotherapy in vivo using BALB/c and C57BL/6 mice, Colon26, a syngeneic endogenously HSP105-expressing colorectal cancer cell line, and B16.F10, a melanoma cell line. The DNA vaccine was used to stimulate HSP105-specific T-cell responses. Fifty percent of mice immunized with the HSP105 DNA vaccine completely suppressed the growth of subcutaneous Colon26 or B16.F10 cells accompanied by massive infiltration of both CD4(+) T cells and CD8(+) T cells into tumors. In cell transfer or depletion experiments we proved that both CD4(+) T cells and CD8(+) T cells induced by these vaccines play critical roles in the activation of antitumor immunity. Evidence of autoimmune reactions was not present in surviving mice that had rejected tumor cell challenges. We found that HSP105 was highly immunogenic in mice and that the HSP105 DNA vaccination induced antitumor immunity without causing autoimmunity. Therefore, HSP105 is an ideal tumor antigen that could be useful for immunotherapy or the prevention of various human tumors that overexpress HSP105, including colorectal cancer and melanoma.