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Johnson, Lexus R.; Lee, Daniel Y.; Eacret, Jacqueline S.; Ye, Darwin; June, Carl H.; Minn, Andy J.
Cell, 09/2021, Letnik: 184, Številka: 19Journal Article
Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens. Display omitted •CAR-T cells deliver RN7SL1 in extracellular vesicles (EVs) and activate RIG-I•CAR-T cells expressing RN7SL1 show greater expansion and persistence and less exhaustion•Preferential uptake of RN7SL1 by DC/myeloid over tumor cells enhances endogenous immunity•CAR-T EVs can co-deliver antigen with RN7SL1 to reject tumors with CAR antigen loss CAR-T cells expressing an immunostimulatory RNA achieve enhanced efficacy in solid tumor mouse models with CAR antigen loss by improving autonomous CAR-T cell function and promoting endogenous immunity through preferential uptake of RNA-containing extracellular vesicles in innate immune cells over tumor cells.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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