Recently, we isolated and expanded a CD8+ T-cell clone from the blood of a patient with regressing renal cell carcinoma following an allogeneic hematopoietic stem cell transplant (HSCT) that killed patient tumor cells in vitro. This CTL clone was found to have tumor specific cytotoxicity, recognizing an HLA-A11-restricted 10-mer peptide named CT-RCC-1. The transcripts encoding this antigen, CT-RCC-8 and CT-RCC-9 were found to be derived from a novel human endogenous retrovirus type E (named CT-RCC HERV-E) located on chromosome 6q. Both transcripts present splice variants that share a common sequence region encoded in the retroviral 5'LTR that is spliced to non-shared regions derived from the protease and polymerase genes, respectively. Remarkably, these transcripts were found to be selectively expressed in the clear cell variant of renal cell carcinoma (ccRCC) with no expression observed in normal tissues or any other type of tumor cell. We have now discovered transcripts encoding the entire envelope gene (env) of the CT-RCC HERV-E provirus are also expressed in ccRCC. Expression of these unique HERV-E env transcripts was detected in kidney cancer cells by RT-PCR, Northern blot, and sequence analysis. The proviral env was found to be expressed concurrent with the previously identified CT-RCC-8 and -9 transcripts, and was only observed in ccRCC cells with no expression observed in any other tumors or normal tissues. We generated 2 peptides derived from the env surface region and 2 peptides derived from the env transmembrane region that were predicted to have a high binding affinity for HLA-A2. Dendritic cells generated from the PBMC of healthy HLA A2+ donors were pulsed with one of these 4 env peptides then were used to stimulate autologous T-cells in vitro. After three stimulations, 3 of these peptides were found to expand CD8+ T-cells that secreted IFN-γ when co-cultured with a HERV-E Env expressing ccRCC tumor cell line transfected to express HLA A2+ but did not secrete IFN-γ against the wild type tumor that was HLA A2 negative.
Conclusion: The envelope of the CT-RCC HERV-E provirus is expressed selectively in ccRCC and encodes highly immunogenic antigens that can be targeted by cytotoxic T-cells. Our data suggests antigens derived from this newly discovered HERV-E envelope could represent excellent targets for T-cell based immunotherapy for kidney cancer.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.