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
Summary
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
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