Department of Pediatrics, Graduate Program in Neuroscience, Biostatistics and Bioinformatics, University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA.
Cancer Res. 2011 Nov 1;71(21):6583-9. doi: 10.1158/0008-5472.CAN-11-1166. Epub 2011 Sep 9.
With recent approval of the first dendritic cell (DC) vaccine for patient use, many other DC vaccine approaches are now being tested in clinical trials. Many of these DC vaccines employ tumor cell lysates (TL) generated from cells cultured in atmospheric oxygen (∼20% O₂) that greatly exceeds levels found in tumors in situ. In this study, we tested the hypothesis that TLs generated from tumor cells cultured under physiologic oxygen (∼5% O₂) would be more effective as a source for DC antigens. Gene expression patterns in primary glioma cultures established at 5% O₂ more closely paralleled patient tumors in situ and known immunogenic antigens were more highly expressed. DCs treated with TLs generated from primary tumor cells maintained in 5% O₂ took up and presented antigens to CD8 T cells more efficiently. Moreover, CD8 T cells primed in this manner exhibited superior tumoricidal activity against target cells cultured in either atmospheric 20% O₂ or physiologic 5% O₂. Together, these results establish a simple method to greatly improve the effectiveness of DC vaccines in stimulating the production of tumoricidal T cells, with broad implications for many of the DC-based cancer vaccines being developed for clinical application.
随着首个树突状细胞 (DC) 疫苗获得患者使用的批准，许多其他的 DC 疫苗方法正在临床试验中进行测试。许多这些 DC 疫苗采用从在大气氧（约 20% O₂）中培养的细胞生成的肿瘤细胞裂解物（TL），这大大超过了原位肿瘤中发现的水平。在这项研究中，我们测试了这样一个假设，即在生理氧（约 5% O₂）下培养的肿瘤细胞生成的 TL 作为 DC 抗原的来源会更有效。在 5% O₂下建立的原代胶质瘤培养物中的基因表达模式更接近原位患者肿瘤，并且已知的免疫原性抗原表达更高。用来自在 5% O₂下培养的原代肿瘤细胞生成的 TL 处理的 DC 更有效地摄取和呈递抗原给 CD8 T 细胞。此外，以这种方式引发的 CD8 T 细胞对在大气 20% O₂或生理 5% O₂中培养的靶细胞表现出优越的杀瘤活性。这些结果共同建立了一种简单的方法，可以大大提高 DC 疫苗刺激产生杀瘤性 T 细胞的有效性，这对许多正在开发用于临床应用的基于 DC 的癌症疫苗具有广泛的意义。
