Overcoming extracellular vesicle-mediated fratricide improves CAR T cell treatment against solid tumors
Menée à l'aide de lignées cellulaires, d'échantillons sanguins, d'échantillons tumoraux et de modèles murins, cette étude met en évidence un mécanisme par lequel de petites vésicules extracellulaires sécrétées par les tumeurs favorisent la destruction des lymphocytes CAR-T en leur transférant des antigènes tumoraux puis démontre l'efficacité antitumorale de lymphocytes CAR-T exprimant la serpine B9
The efficacy of chimeric antigen receptor (CAR) T cells against solid tumors is limited. The molecular mechanisms underlying CAR T cell resistance are yet to be elucidated and new strategies need to be developed to improve treatment outcomes. Here we report that solid tumors respond to CAR T cells by upregulating the secretion of small extracellular vesicles carrying tumor antigens, which are horizontally transferred to CAR T cells, leading to antigen recognition and CAR T cell fratricide. Engineered CAR T cells armored with Serpin B9, a major granzyme B inhibitor, show decreased fratricide and increased vitality, tumor infiltration, and antitumor activity in female mice. Moreover, Serpin B9-armored CAR T cells show higher efficacy than parental CAR T cells in treating solid tumors when combined with the anti-programmed death 1 antibody. Our study demonstrates a mechanism that limits CAR T cell function and suggests an improved strategy in tumor treatment.
Nature Cancer , résumé 2025