Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell Vaccines
Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell Vaccines
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DOI：
10.1002/cncr.22958
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发表时间：
2007-10-01
期刊：
影响因子：
6.2
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
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作者：
Yamaguchi, Shinjiro;Tatsumi, Tomohide;Hayashi, Norio
背景。临床需要进一步优化基于树突状细胞（DC）的疫苗来对抗晚期癌症。鉴于在不同类型的癌症中，特别是在晚期或转移性癌症中，最近发现的肿瘤抗原EphA2的表达水平范围很广，作者在小鼠结肠癌模型中评估了用EphA2衍生肽（EphA2- dc）脉冲DCs接种疫苗的有效性。Western blot分析10例晚期结直肠癌组织中EphA2蛋白的表达水平。C57BL/6小鼠每周免疫2次。干扰素γ (ifn - γ) ELISPOT检测用于分析对epha2衍生肽具有特异性的cd8阳性T细胞。免疫小鼠皮下注射epha2阳性小鼠结肠腺癌（MC38）小鼠结肠肿瘤或epha2阴性BL6黑色素瘤肿瘤。在一些实验中，给小鼠注射抗cd8、抗cd4或抗金牛GM1抗体，以消耗相应的淋巴细胞亚群。在10例晚期结直肠癌中，有6例（60%）EphA2过表达。ifn - γ ELISPOT检测显示，epha2衍生的肽特异性cd8阳性T细胞通过epf - dc免疫产生。与非脉冲dc或磷酸盐缓冲盐水免疫相比，eff - dc免疫可抑制MC38肿瘤生长。相比之下，接种epf - dc对BL6的生长没有影响。抗体耗竭研究显示，cd8阳性T细胞和cd4阳性T细胞，而非自然杀伤细胞，在eff - dcs免疫效果中起关键作用。epf - dc疫苗可对MC38肿瘤细胞的再攻击产生长期的抗肿瘤免疫。目前的结果表明，epf - dc疫苗在癌症环境中可能是一种有希望的预防/治疗方式。
BACKGROUND. Further optimization of dendritic cell (DC)-based vaccines is required clinically against advanced stage cancer. Given the broad range of expression levels observed in the recently defined tumor antigen EphA2 in a diverse types of cancers, especially in advanced stage or metastatic cancers, the authors evaluated the effectiveness of vaccination using DCs pulsed with EphA2-derived peptides (Eph-DCs) in a murine colon cancer model.METHODS. EphA2 protein expression levels were evaluated in advanced colorectal carcinoma tissues from 10 patients by Western blot analysis. C57BL/6 mice were immunized with Eph-DCs twice weekly. Interferon gamma (IFN-gamma) ELISPOT assays were used for the analysis of CD8-positive T cells that were specific for EphA2-derived peptide. Immunized mice were challenged subcutaneously with EphA2-positive murine colorectal adenocarcinoma (MC38) mouse colon tumors or with EphA2-negative BL6 melanoma tumors. In some experiments, mice were injected with anti-CD8, anti-CD4, or antiasialo GM1 antibody to deplete corresponding lymphocyte Subsets.RESULTS. Among 10 samples of advanced colorectal carcinoma, 6 samples (60%) overexpressed EphA2. IFN-gamma ELISPOT assays revealed that EphA2-derived peptide-specific CD8-positive T cells were generated by immunization with Eph-DCs. Immunization with Eph-DCs inhibited MC38 tumor growth compared with immunization using unpulsed DCs or phosphate-buffered saline. In contrast, Eph-DC vaccination had no effect on BL6 growth. Antibody depletion Studies revealed that both CD8-positive T cells and CD4-positive T cells, but not natural killer cells, played critical roles in the efficacy observed for immunizations with Eph-DCs. Eph-DC vaccines resulted in long-term antitumor immunity against a rechallenge with MC38 tumor cells.CONCLUSIONS. The current results demonstrated that Eph-DC vaccines may represent a promising preventative/therapeutic modality in the cancer setting.