电穿孔
免疫疗法
T细胞
癌症研究
癌症免疫疗法
生物
CD8型
嵌合抗原受体
T细胞受体
白细胞介素12
免疫学
细胞毒性T细胞
过继性细胞移植
抗原
免疫系统
基因
体外
生物化学
作者
Irene Olivera,Elixabet Bolaños,Jose Gonzalez-Gomariz,Sandra Hervas-Stubbs,Karina Mariño,Carlos Luri-Rey,Iñaki Etxeberria,Assunta Cirella,Josune Egea,Javier Glez-Vaz,Saray Garasa,Maite Alvarez,Iñaki Eguren-Santamaria,Sonia Guedan,Miguel F. Sanmamed,Pedro Berraondo,Gabriel A. Rabinovich,Alvaro Teijeira,Ignacio Melero
标识
DOI:10.1016/j.xcrm.2023.100978
摘要
Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to express either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly injected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions. These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this intratumoral immunotherapeutic strategy is recapitulated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL-12 and DRIL18 mRNA electroporation.
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