Abstract

Human endogenous retroviruses (HERVs), remnants of ancient germ-line infections with exogenous retroviruses, are estimated to comprise up to 8% of human genome. Most HERVs have accumulated mutations and deletions that prevent their expression as an infectious virus. Nevertheless, a growing number of HERV genes and proteins have been found to be expressed in different cancers, raising the possibility that HERV-derived antigens might represent excellent targets for tumor immunotherapy. Here, we review data showing HERV-encoded antigens are capable of eliciting humoral and T-cells specific antitumor immunity. We also describe a novel HERV-E that was recently found to be selectively expressed in over 80% of clear cell kidney cancer but not in normal tissues. Remarkably, the restricted expression of HERV-E in kidney tumors was found to occur as a consequence of inactivation of the von Hippel–Lindau tumor suppressor. Importantly, antigens derived from this provirus are immunogenic, stimulating cytotoxic T-cells that kill kidney cancer cells in vitro and in vivo. Taken altogether, these data suggest efforts aimed at boosting human immunity against HERV-derived antigens could be used as a strategy to treat advanced tumors including kidney cancer.

Highlights

  • The basis for safe and effective adoptive cell therapy is to identify truly tumor-specific targets to minimize the risk of autoimmunity [1]

  • There is a growing list of evidence indicating that human endogenous retrovirus (HERVs), which under normal conditions are silenced, can be activated in cancer cells, providing a new source of virus-derived antigens to serve as targets for cancer immunotherapy

  • We found that transcriptional up-regulation of HERV-E in clear cell variant of renal cell carcinoma (ccRCC) is associated with inactivation of the von Hippel–Lindau (VHL) gene

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Summary

INTRODUCTION

The basis for safe and effective adoptive cell therapy is to identify truly tumor-specific targets to minimize the risk of autoimmunity [1]. Metastatic kidney cancer appears to be susceptible to immunebased therapy and allogeneic immunotherapy [13, 14], but surprisingly little data exists characterizing the antigens expressed on the tumor cells targeted by immune cells that mediate regression of metastatic renal cancer. We isolated and expanded a CD8+ T-cell (CTL) clone from the blood of a patient with regressing renal cell carcinoma following an allogeneic hematopoietic stem cell transplant that killed patient tumor cells in vitro [11]. This CTL clone was found to have tumor-specific cytotoxicity, recognizing an HLA-A11-restricted 10-mer peptide named CT-RCC-1. Besides the HERV-E virus described above, which appears to elicit antitumor immunity against kidney cancer cells, there exists a growing number of studies showing other endogenous retroviral products can induce antitumor immunity in other tumors

HERVs as targets for antitumor immunity
Findings
CONCLUSION
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