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Energy metabolism and cell motility defect in NK-cells from patients with hepatocellular carcinoma

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Abstract

Functional rescue of NK-cells in solid tumors represents a central aim for new immunotherapeutic strategies. We have conducted a genomic, phenotypic and functional analysis of circulating NK-cells from patients with HCV-related liver cirrhosis and hepatocellular carcinoma. NK-cells were sorted from patients with HCC or liver cirrhosis and from healthy donors. Comparative mRNA gene expression profiling by whole-human-genome microarrays of sorted NK-cells was followed by phenotypic and functional characterization. To further identify possible mediators of NK-cell dysfunction, an in vitro model using media conditioned with patients’ and controls’ plasma was set up. Metabolic and cell motility defects were identified at the genomic level. Dysregulated gene expression profile has been translated into reduced cytokine production and degranulation despite a prevalent phenotype of terminally differentiated NK-cells. NKG2D-downregulation, high SMAD2 phosphorylation and other phenotypic and molecular alterations suggested TGF-β as possible mediator of this dysfunction. Blocking TGF-β could partially restore functional defects of NK-cells from healthy donors, exposed to TGF-β rich HCC patients’ plasma, suggesting that TGF-β among other molecules may represent a suitable target for immunotherapeutic intervention aimed at NK-cell functional restoration. By an unbiased approach, we have identified energy metabolism and cell motility defects of circulating NK-cells as main mechanisms responsible for functional NK-cell impairment in patients with hepatocellular carcinoma. This opens the way to test different approaches to restore NK-cell response in these patients.

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Funding

Italian Association for Cancer Research (AIRC) IG 15485; Accelerator Award 22794 (AIRC, CRUK, AECC).

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Authors and Affiliations

  1. Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

    Alessandra Zecca, Diana Canetti, Valeria Regina & Andrea Olivani

  2. Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy

    Valeria Barili, Valentina Capizzuto, Barbara Zerbato, Raffaele Dalla Valle, Carlo Ferrari & Gabriele Missale

  3. Toxicology and Advanced Diagnostics, Ospedale S. Agostino-Estense, Modena, Italy

    Chiara Carone, Tommaso Trenti & Elisabetta Cariani

Authors
  1. Alessandra Zecca
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  2. Valeria Barili
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  3. Diana Canetti
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  4. Valeria Regina
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  5. Andrea Olivani
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  6. Chiara Carone
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  7. Valentina Capizzuto
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  8. Barbara Zerbato
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  9. Tommaso Trenti
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  10. Raffaele Dalla Valle
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  11. Carlo Ferrari
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  12. Elisabetta Cariani
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  13. Gabriele Missale
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Contributions

AZ was involved in study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and statistical analysis. VB was involved in study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and statistical analysis Diana Canetti was involved in statistical analysis and technical support; VR was involved in statistical analysis and technical support; AO was involved in acquisition of data and analysis and interpretation of data; CC was involved in statistical analysis. VC was involved in technical support; BZ was involved in technical support; TT was involved in funding contribution and critical revision of the manuscript. RDV was involved in acquisition of data and analysis and interpretation of data; CF was involved in critical revision of the manuscript for important intellectual content; EC was involved in study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtained funding and statistical analysis. GM was involved in study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtained funding and study supervision.

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Correspondence to Gabriele Missale.

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CF: Consultant for Gilead, Abbvie, Arrowhead.

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Zecca, A., Barili, V., Canetti, D. et al. Energy metabolism and cell motility defect in NK-cells from patients with hepatocellular carcinoma. Cancer Immunol Immunother 69, 1589–1603 (2020). https://doi.org/10.1007/s00262-020-02561-4

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  • DOI: https://doi.org/10.1007/s00262-020-02561-4

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