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Sufficiently activated mature natural killer cells derived from peripheral blood mononuclear cells substantially enhance antitumor activity
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  • Chuanling Liu,
  • Yingying Li,
  • Yanrong Li,
  • Meng Hu,
  • Haiyan Wang,
  • Shasha Lu,
  • Zhao Li,
  • Dilinuer Dilimulati,
  • Shunchang Jiao,
  • Shelian Lu,
  • Weihong Zhao
Chuanling Liu
Chinese PLA General Hospital
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Yingying Li
Beijing DCTY® Biotech Co., Ltd
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Yanrong Li
Beijing DCTY® Biotech Co., Ltd
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Meng Hu
Beijing DCTY® Biotech Co., Ltd
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Haiyan Wang
Beijing DCTY® Biotech Co., Ltd
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Shasha Lu
Beijing DCTY® Biotech Co., Ltd
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Zhao Li
Beijing DCTY® Biotech Co., Ltd
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Dilinuer Dilimulati
Beijing DCTY® Biotech Co., Ltd
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Shunchang Jiao
Chinese PLA General Hospital
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Shelian Lu
Beijing DCTY® Biotech Co., Ltd

Corresponding Author:[email protected]

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Weihong Zhao
Chinese PLA General Hospital
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Abstract

Background: Peripheral blood-derived natural killer (NK) cells spontaneously lyse tumor cells without prior sensitization. However, NK cells in peripheral blood (PBNK cells) are in a resting state and exhibit inhibitory phenotypes and impaired cytotoxicity. Thus, strengthening the cytotoxic effector function of PBNK cells and improving NK cell expansion in vitro for a convenient allogeneic therapy are essential. Materials and Methods: Pure cytokine activation and expansion of NK cells [super NK (SNK)] from peripheral blood mononuclear cells were studied. Markers of activated and inhibited NK cells and cytokine secretion by NK cells were examined using flow cytometry. NK cell antitumor activity in vitro was assessed using lactate dehydrogenase (LDH) cytotoxicity assay and an Incucyte real-time imaging system. Additionally, the function of SNK cells against ascites caused by ovarian cancer in NOD-Prkdc(em26Cd52)il2rg(em26Cd22)/Nju (NCG) mice were determined. In a further investigation of the differences between PBNK and SNK, the mRNA of both cells was sequenced and analyzed. Results: Human peripheral blood mononuclear cells showed selective NK cell expansion upon cytokine activation and culture. Both SNK and PBNK cells expressed activation markers, but at different levels, and SNK cells secreted more cytokines related to cytotoxicity than PBNK cells did. Accordingly, SNK cells exhibited strong antitumor activity ex vivo and improved NCG mice survival after intraperitoneal ovarian cancer transplantation. Mechanistically, SNK cells expressed more genes associated with nucleotide metabolism, fatty acid, and ATP metabolism than PBNK cells. Conclusion: SNK cells derived from peripheral blood mononuclear cells have sufficiently activated mature characteristics and high antitumor activity, rendering them a highly promising and essential therapeutic approach for cancer treatment. KEYWORDS Natural killer cell; Peripheral blood; Ovarian cancer; Ascites
08 Sep 2023Submitted to Immunity, Inflammation and Disease
22 Sep 2023Submission Checks Completed
22 Sep 2023Assigned to Editor
22 Sep 2023Review(s) Completed, Editorial Evaluation Pending
03 Oct 2023Reviewer(s) Assigned
25 Oct 2023Editorial Decision: Revise Major