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

Abstract

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.

Naturally occurring T-cell-mediated antitumor immune response to LINE-1 antigens in mice that can be enhanced by vaccination and TLR5 agonist

“…However, we cannot be certain whether we are dealing with bone fide innate (i.e., genetically, and developmentally predetermined) or the observed phenomenon is a form of adaptive response, which is developed to spontaneous desilencing of L1 in rare cells with erroneously broken epigenetic control over expression of DNA repeats. Similar uncertainty exists about the origin of circulating antibodies to L1 antigens found in most healthy humans in our recent study 19 Regardless of its innate or adaptive nature, the observed phenomenon is likely to be an important contributor to a battery of natural cancer prevention mechanisms acting in mammals to eradicate cells with desilenced L1 occurring at early stages of transformation 34,42 . In addition to anticancer function, it may have an anti-aging immunosenolytic role clearing organism from senescent cells known to acquire expression of L1 43,44 .…”

“…Since these sites are all behind immunological barriers and, therefore, do not participate in the formation of immune tolerance to autoantigens, one would expect that L1 antigens expressed in tumors should be recognized by the immune system as tumor-associated antigens and induce an adaptive immune response. In fact, in our recent study we found a frequent association of the ongoing carcinogenic process in humans with several cancer types with elevated levels of anti-ORF1p -ORF2p antibodies in blood 19 . Here, we planned to test, using mouse models, whether one could utilize adaptive T-cell response to suppress growth of L1-expressing tumors.…”