LINE-1 ORF1p is a shared and immunogenic antigen in cancer

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Abstract Background Recent clinical trials are beginning to show the potential for therapeutic cancer vaccines directed against tumor associated antigens. However, there is a limited set of well-defined antigens that are shared across tumors. Noncanonical coding elements in the genome that are usually silenced in normal cells potentially represent a rich source of “dark” antigens when expressed and presented to the immune system. LINE-1 elements are repetitive, virus-like genomic sequences that can copy themselves to new genomic loci, and which are reactivated in many cancers. In this study, we explore ORF1p, a protein encoded by LINE-1 elements, as a potential shared cancer vaccine antigen. Methods We assessed the tumor specificity of LINE-1 expression in large scale public RNA-seq data sets and in a curated database of public immunopeptidomics studies. We validated these findings using cell line and tissue data and performed an in vitro vaccination assay using healthy donor PBMCs to test the immunogenicity of ORF1p. Results We found widespread RNA expression of LINE-1 across many tumor types with esophageal cancer showing the most highly elevated expression. We also found widespread MHC class I presentation of ORF1p-derived peptides in a range of tumor types, including esophageal cancer. We validated the tumor specific protein expression of ORF1p in a small set of 5 tumor, 5 matched normal, and 5 healthy esophageal samples. Finally, we demonstrated that dendritic cells pulsed with ORF1p peptides were able to induce interferon gamma production in healthy donor human T cells after repeated stimulation in vitro . Conclusions We present data demonstrating that dark antigens derived from LINE-1 elements are 1) expressed in a cancer tissue-specific manner, 2) detected in immunopeptidomics data (both publicly available and newly generated for this study) and 3) immunogenic in vitro . The tumor specificity and immunogenicity of ORF1p peptides point to their potential as a cancer vaccine antigen.

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