T-Cell "Rejuvenation" Nanovaccine: Enhancing Immunological Memory and Antitumor Responses through Telomere Extension.

Abstract

Replicative senescence in immune cells undermines vaccine efficacy, with telomere attrition recognized as a key factor to cellular senescence. Studies have shown that the extracellular vesicles (EVs) of bone marrow-derived dendritic cells (BMDCs), which contain the telomeric compounds, can promote telomerase-independent T-cell telomere extension via telomere transfer. Based on this mechanism, we designed a long-term memory T-cell vaccine (LMT/OT-II), which is composed of EVs from BMDCs carrying the ovalbumin peptide OT-II. This vaccine not only enhances antigen presentation but also extends T-cell telomere length, enhancing T-cell vitality and restoring youthful characteristics. To further enhance the antitumor effects, we incorporated the immune adjuvant Poly(I:C) to activate T cells. In both young and aged mouse models, the LMT/OT-II + Poly(I:C) effectively suppressed the growth of B16-OVA melanoma and significantly prolonged the survival of the mouse models. We further developed the LMT/Adpgk + Poly(I:C) vaccine based on mouse colon cancer cell (MC38) neoantigen peptide, which also showed promising results in mice. Through telomere transfer to restore T-cell function and enhance immune memory, our study provides a novel and universal strategy for developing more effective and durable T-cell vaccines, particularly for diseases associated with immunosenescence.