Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer
Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer
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DOI：
10.1053/j.gastro.2013.01.020
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发表时间：
2013-05-01
期刊：
影响因子：
29.4
通讯作者：
Novelli, Francesco
中科院分区：
文献类型：
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作者：
Cappello, Paola;Rolla, Simona;Novelli, Francesco
背景与目的：胰腺导管腺癌（PDA）是一种侵袭性肿瘤，患者通常已处于晚期疾病；胰十二指肠切除术后5年生存率较低。超过 60% 的 PDA 患者体内检测到针对 α-烯醇化酶 (ENO1)（一种糖酵解酶）的抗体，ENO1 特异性 T 细胞可抑制小鼠体内人胰腺异种移植肿瘤的生长。我们研究了 ENO1 DNA 疫苗是否能引发抗肿瘤免疫反应并延长自发发展为致命性胰腺癌的小鼠的生存期。方法：我们将编码 ENO1 的质粒（或对照质粒）注射并电穿孔至 4 周龄的 Kras(G12D)/Cre (KC) 小鼠和 Kras(G12D)/Trp53(R172H)/Cre (KPC) 小鼠中（当胰腺上皮内病变在组织学上明显时）。通过组织学、免疫组织化学、酶联免疫吸附测定、流式细胞术以及酶联免疫吸附斑点和细胞毒性测定来分析抗肿瘤体液和细胞反应。通过Kaplan-Meier分析来分析存活率。结果：与给予对照载体的小鼠相比，ENO1 疫苗诱导了抗体和细胞反应，并且 KC 小鼠的存活时间中位数延长了 138 天，KPC 小鼠的存活时间中位数延长了 42 天。根据组织学分析，该疫苗似乎可以减缓肿瘤进展。接种疫苗的小鼠血清中抗 ENO1 免疫球蛋白 G 水平升高，该免疫球蛋白 G 与癌细胞表面结合并诱导补体依赖性细胞毒性。 ENO1 疫苗接种减少了骨髓源性抑制细胞和 T 调节细胞的数量，并增加了 T 辅助细胞 1 和 17 的反应。结论：在胰腺癌遗传模型中，接种 ENO1 DNA 疫苗可引发针对肿瘤的体液和细胞免疫反应，延缓肿瘤进展，并显着延长生存期。这种疫苗接种策略可能会被开发为 PDA 患者的新辅助治疗。
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is an aggressive tumor, and patients typically present with late-stage disease; rates of 5-year survival after pancreaticoduodenectomy are low. Antibodies against alpha-enolase (ENO1), a glycolytic enzyme, are detected in more than 60% of patients with PDA, and ENO1-specific T cells inhibit the growth of human pancreatic xenograft tumors in mice. We investigated whether an ENO1 DNA vaccine elicits antitumor immune responses and prolongs survival of mice that spontaneously develop autochthonous, lethal pancreatic carcinomas. METHODS: We injected and electroporated a plasmid encoding ENO1 (or a control plasmid) into Kras(G12D)/Cre (KC) mice and Kras(G12D)/Trp53(R172H)/Cre (KPC) mice at 4 weeks of age (when pancreatic intraepithelial lesions are histologically evident). Antitumor humoral and cellular responses were analyzed by histology, immunohistochemistry, enzyme-linked immunosorbent assays, flow cytometry, and enzyme-linked immunosorbent spot and cytotoxicity assays. Survival was analyzed by Kaplan-Meier analysis. RESULTS: The ENO1 vaccine induced antibody and a cellular response and increased survival times by a median of 138 days in KC mice and 42 days in KPC mice compared with mice given the control vector. On histologic analysis, the vaccine appeared to slow tumor progression. The vaccinated mice had increased serum levels of anti-ENO1 immunoglobulin G, which bound the surface of carcinoma cells and induced complement-dependent cytotoxicity. ENO1 vaccination reduced numbers of myeloid-derived suppressor cells and T-regulatory cells and increased T-helper 1 and 17 responses. CONCLUSIONS: In a genetic model of pancreatic carcinoma, vaccination with ENO1 DNA elicits humoral and cellular immune responses against tumors, delays tumor progression, and significantly extends survival. This vaccination strategy might be developed as a neoadjuvant therapy for patients with PDA.