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C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer

Author

Listed:
  • Federica Portale

    (Tumor Microenviroment Unit)

  • Roberta Carriero

    (Bioinformatics Unit)

  • Marta Iovino

    (Tumor Microenviroment Unit)

  • Paolo Kunderfranco

    (Bioinformatics Unit)

  • Marta Pandini

    (Tumor Microenviroment Unit
    Humanitas University)

  • Giulia Marelli

    (Tumor Microenviroment Unit)

  • Nicolò Morina

    (Tumor Microenviroment Unit
    Humanitas University)

  • Massimo Lazzeri

    (Urology Unit)

  • Paolo Casale

    (Urology Unit)

  • Piergiuseppe Colombo

    (Department of Pathology)

  • Gabriele Simone

    (Flow Cytometry Core)

  • Chiara Camisaschi

    (Flow Cytometry Core)

  • Enrico Lugli

    (Flow Cytometry Core)

  • Gianluca Basso

    (Genomics Unit)

  • Javier Cibella

    (Genomics Unit)

  • Sergio Marchini

    (Genomics Unit)

  • Matteo Bordi

    (Università Cattolica del Sacro Cuore)

  • Greta Meregalli

    (Tumor Microenviroment Unit)

  • Anna Garbin

    (Tumor Microenviroment Unit)

  • Monica Dambra

    (Immunopathology Lab)

  • Elena Magrini

    (Immunopathology Lab)

  • Wiebke Rackwitz

    (Dresden University of Technology
    German Red Cross Blood Donation Service North-East)

  • Francesco Cecconi

    (Università Cattolica del Sacro Cuore
    Fondazione Policlinico Universitario A. Gemelli)

  • Alessandro Corbelli

    (Istituto di Ricerche Farmacologiche Mario Negri IRCCS)

  • Fabio Fiordaliso

    (Istituto di Ricerche Farmacologiche Mario Negri IRCCS)

  • Jiri Eitler

    (Dresden University of Technology
    German Red Cross Blood Donation Service North-East
    Partner Site Dresden)

  • Torsten Tonn

    (Dresden University of Technology
    German Red Cross Blood Donation Service North-East
    Partner Site Dresden)

  • Diletta Mitri

    (Tumor Microenviroment Unit
    Humanitas University)

Abstract

NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.

Suggested Citation

  • Federica Portale & Roberta Carriero & Marta Iovino & Paolo Kunderfranco & Marta Pandini & Giulia Marelli & Nicolò Morina & Massimo Lazzeri & Paolo Casale & Piergiuseppe Colombo & Gabriele Simone & Chi, 2024. "C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54355-2
    DOI: 10.1038/s41467-024-54355-2
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    References listed on IDEAS

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