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

Abstract LINE-1 (L1) repeats, the most prevalent family of autonomous retrotransposons in mammalian genomes, encode two polypeptides: ORF1p and ORF2p. Although epigenetically repressed in healthy tissues, L1 elements often derepress in tumors, rendering L1 antigens potential targets for anticancer immunotherapy. To explore this potential, we established mouse tumor-derived cell lines expressing either ORF1p or a synthesized protein featuring projected T-cell epitopes of ORF2p, both fused with enhanced green fluorescent protein (EGFP). L1 antigen expression significantly diminished tumorigenicity and stimulated immunocyte infiltration within syngeneic tumors in immunocompetent mice. However, it did not affect cell growth in culture, tumor growth in immunodeficient SCID and RAG mice, or in immunosenescent old mice. Natural T-cell response to L1-expressing cells was enhanced by systemic stimulation of innate immunity by the TLR5 agonist entolimod or immunization with vaccine based on synthetic peptides representing predicted T-cell-reactive epitopes of L1 antigens. Prophylactic anti-L1 vaccination notably postponed tumor onset in MMTV-Her2/neu mouse breast cancer model and suppressed lung metastasis in B16 melanoma models. Additionally, it decelerated the aging-associated frailty index. We assume that intrinsic T-cell-mediated response to L1-expressing cells acts as a tumor suppressor and antiaging mechanism that can be further stimulated by immunomodulatory interventions.