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CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

ABSTRACT: 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.

SUBMITTER: Tarannum M

PROVIDER: S-EPMC11244547 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Tarannum Mubin M Dinh Khanhlinh K Vergara Juliana J Birch Grace G Abdulhamid Yasmin Z YZ Kaplan Isabel E IE Ay Oyku O Maia Andreia A Beaver Owen O Sheffer Michal M Shapiro Roman R Ali Alaa Kassim AK Dong Han H Ham James Dongjoo JD Bobilev Eden E James Sydney S Cameron Amy B AB Nguyen Quang-De QD Ganapathy Suthakar S Chayawatto Chayapatou C Koreth John J Paweletz Cloud P CP Gokhale Prafulla C PC Barbie David A DA Matulonis Ursula A UA Soiffer Robert J RJ Ritz Jerome J Porter Rebecca L RL Chen Jianzhu J Romee Rizwan R

Science advances 20240712 28

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. ...[more]

PMID: 38996027

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Project description:Background:Cationic solid lipid nanoparticles (SLN) have attracted intensive interest as an effective gene delivery system for its high biocompatibility, stability and low cytotoxicity. In our previous study, we successfully prepared SLN-STAT3 decoy ODN complexes and made a primary study on its antitumor behavior in ovarian cancer cells in vitro. However, there is little information available so far about the effect of SLN-STAT3 decoy ODN complexes on ovarian cancer in vivo, either little information about the pharmacological toxicology in vivo. Material and Methods:We applied nanotechnology to improve the gene delivery system and synthesize SLN-STAT3 decoy ODN complexes. Xenograft mouse models were established to assess the antitumor effects of SLN-STAT3 decoy ODN on the tumor growth of ovarian cancer in vivo. To analyze the mechanisms of SLN-STAT3 decoy ODN, we investigated apoptosis, autophagy, epithelial-mesenchymal transition (EMT) in tumor tissues of nude mice and investigated the effects and toxicology of SLN-STAT3 decoy ODN complexes on the vital organs of nude mice. Results:The results showed that SLN-STAT3 decoy ODN complexes markedly inhibited tumor growth in vivo. SLN-STAT3 decoy ODN complexes could induce cell apoptosis through downregulating Bcl-2, survivin and pro caspase 3, but upregulating Bax and cleaved caspase 3. These complexes could also regulate autophagy through upregulating LC3A-II, LC3B-II and beclin-1, but downregulating p-Akt and p-mTOR. Moreover, these complexes could inhibit cancer cell invasion through reversing EMT. Besides, SLN-STAT3 decoy ODN complexes showed no obvious toxicity on vital organs and hematological parameters of nude mice. Conclusion:The molecular mechanisms that SLN-STAT3 decoy ODN complexes inhibit tumor growth involved activating the apoptotic cascade, regulating autophagy, and reversing EMT program; and these complexes showed no obvious toxicity on nude mice. Our study indicated that the nanocomplexes SLN-STAT3 decoy ODN might be a promising therapeutic approach for ovarian cancer treatment.

Dataset Information

CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Publications

CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

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