Department of Pediatrics, Yale University, New Haven, CT 06510, USA.
Proc Natl Acad Sci U S A. 2010 May 11;107(19):8718-23. doi: 10.1073/pnas.0915086107. Epub 2010 Apr 19.
OCT4 is a transcription factor critical for the pluripotency of human embryonal stem (ES) and induced pluipotency stem (IPS) cells. OCT4 is commonly expressed in germ-cell tumors as well as putative cancer stem cells in several tumors, and is a key determinant of oncogenic fate in germ-cell tumors. The capacity of the human immune system to recognize this critical stem-cell gene is not known, but has implications for preventing tumors with ES/IPS-based therapies and targeting stem-cell pathways in cancer. Here we show that OCT4-specific T cells can be readily detected in freshly isolated T cells from most (>80%) healthy donors. The reactivity to OCT4-derived peptides resides primarily in the CD45RO(+) memory T-cell compartment and consists predominantly of CD4(+) T cells. T cells reactive against OCT4-derived peptides can be readily expanded in culture using peptide-loaded dendritic cells. In contrast to healthy donors, immunity to OCT4 was detected in only 35% of patients with newly diagnosed germ-cell tumors. However, chemotherapy of germ-cell tumors led to the induction of anti-OCT4 immunity in vivo in patients lacking such responses at baseline. These data demonstrate the surprising lack of immune tolerance to this critical pluripotency antigen in humans. Harnessing natural immunity to this antigen may allow immune-based targeting of pluripotency-related pathways for prevention of cancers, including those in the setting of ES/IPS-based therapies.
OCT4 是一种转录因子，对人类胚胎干细胞（ES）和诱导多能干细胞（IPS）的多能性至关重要。OCT4 在生殖细胞肿瘤以及几种肿瘤中的假定癌症干细胞中普遍表达，是生殖细胞肿瘤中致癌命运的关键决定因素。人类免疫系统识别这个关键干细胞基因的能力尚不清楚，但对于预防基于 ES/IPS 的治疗方法的肿瘤和针对癌症干细胞途径具有重要意义。在这里，我们表明 OCT4 特异性 T 细胞可以在大多数（>80%）健康供体的新鲜分离的 T 细胞中轻易检测到。对 OCT4 衍生肽的反应主要存在于 CD45RO(+)记忆 T 细胞区室中，主要由 CD4(+) T 细胞组成。使用负载肽的树突状细胞可以轻易地在培养物中扩增针对 OCT4 衍生肽的 T 细胞。与健康供体相比，在新诊断的生殖细胞肿瘤患者中仅检测到 35%的患者对 OCT4 具有免疫性。然而，生殖细胞肿瘤的化疗导致在基线时缺乏这种反应的患者体内体内诱导抗-OCT4 免疫。这些数据表明，人类对这种关键多能性抗原缺乏免疫耐受性，令人惊讶。利用对这种抗原的天然免疫可能允许针对多能性相关途径进行免疫靶向，以预防癌症，包括基于 ES/IPS 的治疗方法的癌症。
