Science advances · 2024
CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Tarannum Mubin, Dinh Khanhlinh, Vergara Juliana, Birch Grace, Abdulhamid Yasmin Z, Kaplan Isabel E, Ay Oyku, Maia Andreia, Beaver Owen, Sheffer Michal, Shapiro Roman, Ali Alaa Kassim, Dong Han, Ham James Dongjoo, Bobilev Eden, James Sydney, Cameron Amy B, Nguyen Quang-De, Ganapathy Suthakar, Chayawatto Chayapatou, Koreth John, Paweletz Cloud P, Gokhale Prafulla C, Barbie David A, Matulonis Ursula A, Soiffer Robert J, Ritz Jerome, Porter Rebecca L, Chen Jianzhu, Romee Rizwan
Аннотация
Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.