Cancer relevance of circulating antibodies against LINE-1 antigens in humans

LINE-1 (L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues but frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. Here, we established an immunoassay for detecting circulating autoantibodies against L1 proteins in human blood. Using this assay in >3,000 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers compared to healthy individuals. Remarkably, elevated levels of anti-ORF1p-reactive IgG were observed in cancer patients with disease stages 1 and 2, indicating that immune response to L1 antigens can occur at early phases of carcinogenesis. We conclude that the antibody response against L1 antigens could contribute to the diagnosis and determination of immunoreactivity of tumors among cancer types that frequently escape early detection.