Yamaguchi Shinjiro, Tatsumi Tomohide, Takehara Tetsuo, Sakamori Ryotaro, Uemura Akio, Mizushima Tsunekazu, Ohkawa Kazuyoshi, Storkus Walter J, Hayashi Norio
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Cancer. 2007 Oct 1;110(7):1469-77. doi: 10.1002/cncr.22958.
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.
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.
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.
The current results demonstrated that Eph-DC vaccines may represent a promising preventative/therapeutic modality in the cancer setting.
临床上需要进一步优化基于树突状细胞（DC）的疫苗以对抗晚期癌症。鉴于最近在多种类型癌症，尤其是晚期或转移性癌症中观察到的肿瘤抗原EphA2表达水平范围广泛，作者在小鼠结肠癌模型中评估了用EphA2衍生肽脉冲的DC（Eph-DC）进行疫苗接种的有效性。
通过蛋白质免疫印迹分析评估10例晚期结直肠癌组织中EphA2蛋白的表达水平。每周两次用Eph-DC免疫C57BL/6小鼠。采用干扰素γ（IFN-γ）酶联免疫斑点分析（ELISPOT）来分析对EphA2衍生肽具有特异性的CD8阳性T细胞。用EphA2阳性的小鼠结肠腺癌（MC38）小鼠结肠癌肿瘤或EphA2阴性的BL6黑色素瘤肿瘤对免疫小鼠进行皮下攻击。在一些实验中，给小鼠注射抗CD8、抗CD4或抗唾液酸GM1抗体以耗尽相应的淋巴细胞亚群。
在10份晚期结直肠癌样本中，6份样本（60%）EphA2过表达。IFN-γ ELISPOT分析显示，用Eph-DC免疫可产生EphA2衍生肽特异性CD8阳性T细胞。与用未脉冲的DC或磷酸盐缓冲盐水免疫相比，用Eph-DC免疫可抑制MC38肿瘤生长。相比之下，Eph-DC疫苗接种对BL6生长没有影响。抗体耗竭研究表明，CD8阳性T细胞和CD4阳性T细胞而非自然杀伤细胞在Eph-DC免疫观察到的疗效中起关键作用。Eph-DC疫苗可产生针对MC38肿瘤细胞再次攻击的长期抗肿瘤免疫力。
目前的结果表明，Eph-DC疫苗可能是癌症治疗中一种有前景的预防/治疗方式。
