Divison of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
Cancer Res. 2012 Apr 1;72(7):1717-27. doi: 10.1158/0008-5472.CAN-11-3758. Epub 2012 Feb 14.
Due to the exquisite specificity and potency of the immune system, vaccination is in theory the most precise and powerful approach for controlling cancer. However, current data from clinical trials indicate that vaccination rarely yields significant benefits for cancer patients in terms of tumor progression and long-term survival. The poor clinical outcomes of vaccination are primarily caused by mechanisms of immune tolerance, especially within the tumor microenvironment. Here, we report that vaccination drives the evolution of tumor cells toward an immune-resistant and stem-like phenotype that promotes tumor growth and nullifies the CTL response. The emergence of this phenotype required the transcription factor Nanog, which is induced as a consequence of immune selection. Nanog expression enhanced the stem-like features of tumor cells and protected them from killing by tumor-reactive CTLs. Delivery of siNanog into tumor-bearing mice rendered the tumor vulnerable to immune surveillance and strongly suppressed its growth. Together, our findings show tumor adaptation to vaccination through gain of an immune-resistant, stem-like phenotype and identify Nanog as a central molecular target in this process. Future vaccination technology should consider Nanog an important target to enhance the immunotherapeutic response.
由于免疫系统的精确性和高效性，疫苗接种从理论上讲是控制癌症最精确、最有效的方法。然而，目前临床试验的数据表明，疫苗接种很少能给癌症患者的肿瘤进展和长期生存带来显著益处。疫苗接种的临床效果不佳主要是由免疫耐受机制引起的，尤其是在肿瘤微环境中。在这里，我们报告称，疫苗接种促使肿瘤细胞向具有免疫抵抗性和干细胞样表型的方向进化，从而促进肿瘤生长并使 CTL 反应失效。这种表型的出现需要转录因子 Nanog，它是作为免疫选择的结果而被诱导产生的。Nanog 的表达增强了肿瘤细胞的干细胞样特征，并保护它们免受肿瘤反应性 CTL 的杀伤。将 siNanog 递送到荷瘤小鼠中，使肿瘤容易受到免疫监视，并强烈抑制其生长。总之，我们的研究结果表明，肿瘤通过获得具有免疫抵抗性和干细胞样表型来适应疫苗接种，并确定 Nanog 是该过程中的一个关键分子靶点。未来的疫苗接种技术应将 Nanog 视为增强免疫治疗反应的重要靶点。
