Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity

Hu, Mengying, Liu, Di-Ao, Wortzel, Inbal, Collier, Paul, Nelson, Theodore M, Foox, Jonathan, Zhong, Guojie, Tobias, Gabriel, Asao, Tetsuhiko, Bojmar, Linda, Kenific, Candia M, Wang, Gang, Caielli, Simone, Wan, Zurong, Qureshy, Sarah, Reed, Max, Piszczatowski, Richard, Ravisankar, Purnima, Brown, Julia A, Xiong, Sihan, Wang, Huajuan, Lauritzen, Pernille, Aylon, Yael, Molina, Henrik, Jarnagin, William R, Oren, Moshe, Stanger, Ben Z, Bui, Jack, Bergers, Gabriele, Noël, Agnès, Grandgenett, Paul M, Hollingsworth, Michael A, Tuveson, David, Boudreau, Nancy, Bromberg, Jacqueline, Kelsen, David, Jones, David R, Santambrogio, Laura, Zeng, Melody Y, Pascual, Virginia, Kim, Han Sang, Mason, Christopher E, Zhang, Haiying, Matei, Irina R, Lyden, David (April 2026) Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity. Cancer Cell. S1535-6108(26)00177. ISSN 1535-6108

PDF 10.1016.j.ccell.2026.03.023.pdf - Published Version Available under License Creative Commons Attribution Non-commercial. Download (13MB)

Abstract

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders
CSHL Authors:	Tuveson, David A.
Communities:	CSHL labs > Tuveson lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	30 April 2026
Date Deposited:	12 May 2026 14:30
Last Modified:	12 May 2026 14:30
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42200

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