Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells
Yoshiyuki Takahashi, Nanae Harashima, Sachiko Kajigaya, Hisayuki Yokoyama, Elena Cherkasova, J. Philip McCoy, Ken-ichi Hanada, Othon Mena, Roger Kurlander, Tawab Abdul, Ramaprasad Srinivasan, Andreas Lundqvist, Elizabeth Malinzak, Nancy Geller, Michael I. Lerman, Richard W. Childs
Yoshiyuki Takahashi, Nanae Harashima, Sachiko Kajigaya, Hisayuki Yokoyama, Elena Cherkasova, J. Philip McCoy, Ken-ichi Hanada, Othon Mena, Roger Kurlander, Tawab Abdul, Ramaprasad Srinivasan, Andreas Lundqvist, Elizabeth Malinzak, Nancy Geller, Michael I. Lerman, Richard W. Childs
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Research Article Oncology

Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells

Abstract

Transplanted donor lymphocytes infused during hematopoietic stem cell transplantation (HSCT) have been shown to cure patients with hematological malignancies. However, less is known about the effects of HSCT on metastatic solid tumors. Thus, a better understanding of the immune cells and their target antigens that mediate tumor regression is urgently needed to develop more effective HSCT approaches for solid tumors. Here we report regression of metastatic renal cell carcinoma (RCC) in patients following nonmyeloablative HSCT consistent with a graft-versus-tumor effect. We detected RCC-reactive donor-derived CD8+ T cells in the blood of patients following nonmyeloablative HSCT. Using cDNA expression cloning, we identified a 10-mer peptide (CT-RCC-1) as a target antigen of RCC-specific CD8+ T cells. The genes encoding this antigen were found to be derived from human endogenous retrovirus (HERV) type E and were expressed in RCC cell lines and fresh RCC tissue but not in normal kidney or other tissues. We believe this to be the first solid tumor antigen identified using allogeneic T cells from a patient undergoing HSCT. These data suggest that HERV-E is activated in RCC and that it encodes an overexpressed immunogenic antigen, therefore providing a potential target for cellular immunity.

Authors

Yoshiyuki Takahashi, Nanae Harashima, Sachiko Kajigaya, Hisayuki Yokoyama, Elena Cherkasova, J. Philip McCoy, Ken-ichi Hanada, Othon Mena, Roger Kurlander, Tawab Abdul, Ramaprasad Srinivasan, Andreas Lundqvist, Elizabeth Malinzak, Nancy Geller, Michael I. Lerman, Richard W. Childs

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Figure 6

Identification of the peptide recognized by CTL expanded from a responding patient and detection of circulating CT-RCC-1 peptide–specific T cells after HSCT.

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Identification of the peptide recognized by CTL expanded from a respondi...
A 10-amino-acid HERV-E–derived peptide (CT-RCC-1) expressed on RCC was identified to be the target antigen of tumor-reactive CTL. (A) The position of the peptide was identified to be located in frame 2 of the 375-bp CT-RCC common region. (B) Four candidate peptides were synthesized from the predicted amino acid translations of these minigenes; only the 10-mer peptide ATFLGSLTWK induced dose-dependent IFN-γ production by SAUJ-RCC–reactive CTLs. (C) RCC-reactive SAUJ-CTL was generated by stimulating SAUJ-PBMCs (day +1,213) with irradiated SAUJ-RCC cells followed by flow sorting for TCR-Vβ7+CD8+ T cells. These CTLs were stained with a PE-conjugated HLA-A*1101/CT-RCC-1 (ATFLGSLTWK) tetramer; 56.6% of the CD3+CD8+ cells in this CTL line had antigen specificity for the CT-RCC-1 peptide. (D) PBMCs collected from SAUJ before HSCT did not bind to the CT-RCC-1 tetramer. CT-RCC-1–specific T cells were detected by tetramer analysis after HSCT in patient SAUJ on days +913 and +1,213 following tumor regression, constituting 1.12% and 0.48% of the CD3+CD8+ T cell repertoire, respectively.