Abstract SY24-01: Pluripotency genes as targets for cancer prevention

Abstract

Abstract Recent studies have suggested an overlap between the core pathways that maintain pluripotency in embryonal stem (ES) or induced pluripotency stem (iPS) cells and those implicated in oncogenesis. The presence of ES/iPS signature genes can be demonstrated in diverse cancers and correlates with a poorer outcome. The ES pathways have been shown to be particularly expressed in the putative cancer stem cell (CSC) population within the tumor bulk. Therefore pathways that regulate stemness are being actively targeted in human cancer. Here, I will discuss evidence for immune-mediated targeting of the core ES genes, such as OCT4 and SOX2 in humans. Initial studies suggested that humoral and cellular responses against SOX2 can be detected in patients with preneoplastic monoclonal gammopathy of undetermined significance (MGUS). Presence of anti-SOX2 T cell responses correlated with reduced risk of progression to clinical myeloma. Surprisingly, T cell responses against OCT4, a common marker of ES cells, can be readily detected in healthy human donors. OCT4-specific T cell response resides predominantly in the CD4+ T cell compartment and comprises of CD45RO+ memory T cells. These T cells can be readily expanded in culture using autologous dendritic cells loaded with OCT4-expressing germ cell tumors. In contrast to the finding with healthy donors, T cell immunity to OCT4 is deficient in freshly isolated circulating T cells from patients with germ cell tumors (GCTs). However, these T cells can be observed after chemotherapy-induced cell death of tumor cells in vivo. The capacity of the human immune system to target both of the core pluripotency genes (SOX2 and OCT4) may facilitate harnessing the immune system against GCTs and putative CSCs in diverse tumor types. ES-associated genes such as OCT4 seem to be dispensable for the function of adult stem cells in mice, suggesting that targeting these genes in the setting of cancer might not carry adverse effects against normal adult stem cells. As these immune responses seem to be engaged during early stages of carcinogenesis, including in preneoplastic states, we suggest that they may also be particularly attractive targets for immune-mediated cancer prevention in diverse high-risk settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY24-01. doi:10.1158/1538-7445.AM2011-SY24-01