Cancer immunotherapies such as anti-PD-1 and anti-CTLA-4 antibodies have revolutionized outcomes for patients that in many cases were previously bleak. They have shown particular efficacy in melanoma, often delivering robust responses in advanced stages of disease. However, it is still only a proportion of patients that actually respond to treatment, leaving a wide scope for additional and combination therapies to fill the breach.
For these clinically successful therapies to work, recognition of antigens present on cancer cells is a necessary prerequisite. Aside from mutation-derived neoantigens, shared cancer-testis antigens (CTAg) provide crucial targets for future therapeutic development, either as novel vaccination agents or in combination with immune checkpoint blockade. Here we identify the CTAg ropporin-1 (ROPN1) as a viable target in metastatic melanoma. Patients with advanced metastatic disease showed high ROPN1 expression which was able to engage both humoral and cellular arms of the immune response.
Specifically, 85% of patients tested (n=67) had ROPN1 protein expression in their tumour, as shown by multi-colour immuno-histochemistry. 51% of patients (n=104) had a detectable ROPN1-specific humoral response, with antibody titres that increased with disease stage. Analysis of TCGA data confirmed the high prevalence of ROPN1 expression among melanoma patients at various stages of disease.
Strong multi-epitope CD4+ and CD8+ T cell responses were also elicited. Of these, we determined ROPN1163-171 to be a novel immunogenic HLA-A*0201 restricted CD8+ T cell epitope. In addition, a ROPN1-specific T cell line was used to identify the CD8+ T cell receptor (TCR) sequences that recognize this epitope.
In conclusion, ROPN1 is an ideal therapeutic target due to its frequent yet cancer-specific expression. Its high immunogenicity lends itself to being an attractive choice for peptide vaccination therapy either alone or in combination with immune checkpoint blockade.