Unveiling the immunogenicity of the dark immunopeptidome of melanoma

Almost 40%-50% of melanoma patients do not respond or can develop resistance to current checkpoint inhibition immunotherapy. While antigen-based immunotherapy has shown great potential in cancer treatment, this heavily relies on the understanding of melanoma-specific antigenic peptides presented on the surface of the cancer cells. In contrast to the conventional origins of the antigenic peptides, studies have suggested that a proportion of such potential tumour-specific peptide antigens derive from non-canonical translation products, such as translated 5′ or 3’ UTRs, exon–exon junctions, intronic regions, non-canonical reading frames or antisense transcripts. Using state-of-the-art multiomic (i.e., genomics, transcriptomics, proteomics, and immunopeptidomics) and computational techniques, this project will identify such ‘cryptic’ peptide antigens that are derived from non-canonical sources in patient-derived melanoma cell lines, xenograft models, plasma samples from Stage 3/4 melanoma patients on checkpoint inhibition immunotherapy. The immunogenicity of these cryptic peptides will be assessed using these patients’ peripheral blood mononuclear cells by examining their immune responses to these peptides, thereby characterising melanoma-associated peptides correlated with responsiveness to checkpoint inhibition regimes. This project will provide immunogenic peptide candidates for next-generation antigen-based melanoma immunotherapy and peptide biomarkers for predicting the immunotherapy outcomes.