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Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection

Cellular & Molecular Immunology volume 20, pages 895–907 (2023)Cite this article

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Abstract

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules; stronger cytotoxicity against HCMV-infected fibroblasts; and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32–0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18–0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

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Acknowledgements

We thank Mr. Chuan-Yu Zhang (iCELL Co., Ltd., Beijing, China) for his help in the organization of the expansion of NK cells. We also thank BeiGene Co., Ltd. (Beijing, China) for providing anti-PD-1, anti-TIGIT and anti-Tim3 antibodies. This work was supported by the National Key Research and Development Program of China (grant 2022YFA1103300), Major of the National Natural Science Foundation of China (No.82293630), Key Program of the National Natural Science Foundation of China (No. 81930004), and National Natural Science Foundation of China (grants 81870140, 82070184, 82270228 and 81370666). It was further supported through the Peking University People’s Hospital Research and Development Funds (grant RDX2019-14; RDL2021-01). We thank the core facilities at the Peking University Institute of Hematology for sample collection.

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Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China

    Qian-Nan Shang, Xing-Xing Yu, Zheng-Li Xu, Yu-Hong Chen, Ting-Ting Han, Yuan-Yuan Zhang, Meng Lv, Yu-Qian Sun, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiang-Yu Zhao & Xiao-Jun Huang

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Qian-Nan Shang, Xing-Xing Yu & Xiao-Jun Huang

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Contributions

Q-NS conducted the in vitro experiments and animal experiments and performed the statistical analyses. X-XY conducted flow cytometry assays and facilitated in vitro experiments. Z-LX, Y-HC, T-TH, Y-YZ, ML, Y-QS, YW, L-PX and X-HZ performed the clinical examinations. X-JH and X-YZ designed the study and interpreted the data. X-JH, X-YZ and Q-NS wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiang-Yu Zhao or Xiao-Jun Huang.

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Shang, QN., Yu, XX., Xu, ZL. et al. Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection. Cell Mol Immunol 20, 895–907 (2023). https://doi.org/10.1038/s41423-023-01046-5

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