Natural immunity to pluripotency antigen OCT4 in humans

Abstract

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/IPSbased therapies.

The Tumor Antigen Cyclin B1 Hosts Multiple CD4 T Cell Epitopes Differently Recognized by Pre-Existing Naive and Memory Cells in Both Healthy and Cancer Donors

“…They also did not generate a huge number of T cell lines when pools of peptides were used as immunogens, suggesting that either these T cells are not able to be expanded or that our culture conditions are not appropriate for their expansion. Spontaneous CD4 T cell responses to the cancer Ag OCT4 or MUC-1 have already been observed in healthy donors (43,44), but remained unusual as compared with other tumor Ags (8,11,12,45,46). For the first time, to our knowledge, we demonstrated that the spontaneous CD4 T cell response to CCNB1 persists in cancer patients and is not therefore dampened by the tumors.…”

Human iPS cell–derived hematopoietic progenitor cells induce T-cell anergy in in vitro–generated alloreactive CD8+ T cells

“…However, iPSCs express high levels of Oct4, which has been suggested to contribute to T-cell responses to iPSCs. 53 It will therefore be beneficial to design new reprogramming approaches that reduce Oct4 expression.…”

Generation of pluripotent stem cells via protein transduction

“…These results showed that iPSCs has higher immunogenicity than ESCs, and iPSCs produced via retroviral methods are more immunogenic than those generated via non-integrating elements. Research has also shown that humans immune system has natural immunity to pluripotency antigen Oct4 (Dhodapkar et al, 2010). Therefore, the high immunogenicity of genomic integration iPSCs may be caused by the sustained expression of the exogenous transcription factors.…”