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Endogenous retrovirus sequences as a novel class of tumor-specific antigens: an example of HERV-H env encoding strong CTL epitopes

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Abstract

Our genome consists to about 8% of human endogenous retroviral (HERV) sequences. These HERVs have been discussed to be linked to human diseases for decades. Recently, a detailed analysis of a HERV-H sequence located on chromosome Xp22.3 revealed a strong expression in a subset of gastrointestinal cancers whereas expression in normal tissues and in other cancer entities was low. In the present study, we used the reverse immunology approach to test the immunological potential of this HERV-H ORF on Xp22.3. A total of ten peptides displaying HLA-A2.1-binding motifs were selected from the predicted env protein sequence. Stimulation of peripheral T cells with retroviral peptides (RVPs) presented by autologous antigen-presenting cells clearly resulted in sustained proliferation of predominantly CD8+ T cells. High numbers of IFN-γ-secreting T cells were detectable after several weekly stimulations with RVP mixes. Reactivity observed in RVP-Mix–stimulated cultures was attributable to RVP03, RVP09 and to a lower extend to RVP08, suggesting those to be highly immunogenic epitopes. Besides killing of RVP-loaded target cells, up to 40% specific lysis of colorectal carcinoma cell lines endogenously expressing this HERV-H Xp22.3 ORF was achieved. These data demonstrate that human T cells can be sensitized toward HERV peptides and moreover posses a high lytic potential toward HERV-H expressing CRC cells. Additionally, these data hint toward endogenous ENV protein expression followed by proteasomal degradation and presentation in the context of HLA molecules. Finally, our data strengthen the view that HERV-encoded sequences should be considered as a new class of tumor-specific antigens.

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Acknowledgments

Thanks to Michael Mullins for his editing advice as a native speaker and proofreading of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The authors declare that all experiments on human subjects were conducted in accordance with the Declaration of Helsinki and that all procedures were carried out with the adequate understanding and written consent of the subjects.

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Authors and Affiliations

  1. Department of General, Thoracic, Vascular and Transplantation Surgery, Section Molecular Oncology and Immunotherapy, University of Rostock, Schillingallee 35, 18057, Rostock, Germany

    Christina S. Mullins & Michael Linnebacher

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  1. Christina S. Mullins
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  2. Michael Linnebacher
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Correspondence to Michael Linnebacher.

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Mullins, C.S., Linnebacher, M. Endogenous retrovirus sequences as a novel class of tumor-specific antigens: an example of HERV-H env encoding strong CTL epitopes. Cancer Immunol Immunother 61, 1093–1100 (2012). https://doi.org/10.1007/s00262-011-1183-3

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