Systematic identification of lincRNA-derived immunogenic peptides in melanoma

The search for reliable shared tumor-specific antigens (TSAs) to improve cancer immunotherapy is on-going. The so-called non-coding regions of the genome have recently been shown to give rise to immunogenic peptides, including the melanoma-specific antigen MELOE-1 which is translated from the long intergenic non-coding RNA (lincRNA) meloe in an IRES-dependent manner. Here, we present a strategy to systematically identify tumor-specific antigens produced by ORFs within lincRNAs with IRES-like upstream structures. We provide evidence suggesting that in the melanocytic lineage a significant proportion of the selected lincRNAs can produce immunogenic peptides. T cell repertoires against some of these peptides were found in peripheral blood mononuclear cells (PBMCs) from healthy donors and melanoma patients, and in tumor-infiltrating lymphocytes (TILs) from metastatic melanoma patients. Finally, CD8+ T cell lines from melanoma patients specific for three of the characterized HLA-A *0201 epitopes could recognize melanoma cell lines, which were enhanced by reticular stress. Thus, these peptides may represent a new class of shared TSAs in melanoma and are attractive candidates for evaluation as targets for immunotherapy in preclinical studies. In addition, our selection strategy has the potential to identify new lincRNA-derived antigens in other cancers.