Background: Despite impressive responses to checkpoint inhibition in melanoma, it is clear that some patients require additional strategies to produce clinically-effective immune responses. Here we describe ropporin, a tissue-restricted and highly expressed antigen in malignant melanoma.
Results: ROPN isoforms were minimally expressed in normal tissues other than testis. Melanoma tumours and cell lines derived from metastatic lesions showed high levels of both ROPN1 gene and protein expression. Sera obtained from patients with advanced melanoma revealed frequent presence of ROPN1 and ROPN1B specific antibodies. We identified both CD4+ and CD8+ ROPN-specific T cell responses in patient-derived peripheral blood mononuclear cells, and defined a minimal HLA-A*0201 restricted epitope recognised by CD8+ T cells. ROPN specific CD8+ T cells were generated, and could kill ROPN+, but not ROPN-, melanoma cell lines in vitro. Furthermore we demonstrated that escape from T cell killing due to loss of the Melan A antigen following epithelial-to-mesenchymal transition, did not occur for ROPN specific T cell targeting.
Conclusion: ROPN is a highly immunogenic and tumour-specific protein commonly found in melanomas. The identification of cognate T cell responses to ROPN in melanoma patient-derived lymphocytes, and the ability of such T cells to kill ROPN+ melanoma, demonstrates the potential of this antigen for immune targeting of melanoma. Furthermore mesenchymal-like melanomas, classically considered to be treatment resistant, were consistently killed by ROPN specific T cells. ROPN thus represents a promising immunotherapeutic target which may be a useful adjunct to checkpoint inhibition.