T cells weaponize DNA packets to boost tumor immunity, opening new cancer treatment path
Researchers discovered that activated T cells release vesicles containing DNA that reprogram immune cells to fight cancer more effectively. The finding could unlock a new class of cell-free immunotherapy drugs and rescue patients who fail to respond to existing checkpoint inhibitor treatments.
Originaltitel: Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity
Aktiverade T-cellsvesiklar överför DNA som förbättrar antigenprocessering och tumörimunitet. Forskare har identifierat att extracellulära vesiklar från aktiverade T-celler innehåller dubbelsträngat DNA berikad på immunkodande gener, framför allt sådana som styr antigenprocessering och antalet. Vid cellupptagning levererar enzymet granzym B DNA in i cellkärnan, där det tillfälligt uttrycks för att öka antigenprocessering och T-cellaktivering. DNas-behandling tar bort detta DNA och blockerar effekten, vilket bekräftar mekanismen. Weill Cornell Medical, Ohio State University och Memorial Sloan Kettering Cancer Center utvecklar T-cellvesiklarna som acellulär immunterapi. Potentialen ligger i att synergera med checkpoint-blockerare hos tumörer resistenta mot current-behandling, utan att öka autoimmunsvar. För biopharmaföretag öppnas vägen till nästa generations cellulär-fri immunterapi med reducerad tillverkningskomplexitet.
<p>Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. ATEV-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EVDNA), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by ATEVs disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EVDNA encoding APP genes. DNase treatment removes most AT-EVDNA, abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, ATEVs hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by ATEVs that boosts APP and anti-tumor immunity while limiting autoimmunity.</p>