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

Federica Portale, Roberta Carriero, Marta Iovino, Paolo Kunderfranco, Marta Pandini, Giulia Marelli, Nicolò Morina, Massimo Lazzeri, Paolo Casale, Piergiuseppe Colombo, Gabriele Simone, Chiara Camisaschi, Enrico Lugli, Gianluca Basso, Javier Cibella, Sergio Marchini, Matteo Bordi, Greta Meregalli, Anna Garbin, Monica Dambra, Elena Magrini, Wiebke Rackwitz, Francesco Cecconi, Alessandro Corbelli, Fabio Fiordaliso, Jiri Eitler, Torsten Tonn and Diletta Mitri ()
Additional contact information
Federica Portale: Tumor Microenviroment Unit
Roberta Carriero: Bioinformatics Unit
Marta Iovino: Tumor Microenviroment Unit
Paolo Kunderfranco: Bioinformatics Unit
Marta Pandini: Tumor Microenviroment Unit
Giulia Marelli: Tumor Microenviroment Unit
Nicolò Morina: Tumor Microenviroment Unit
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
Francesco Cecconi: Università Cattolica del Sacro Cuore
Alessandro Corbelli: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Fabio Fiordaliso: Istituto di Ricerche Farmacologiche Mario Negri IRCCS
Jiri Eitler: Dresden University of Technology
Torsten Tonn: Dresden University of Technology
Diletta Mitri: Tumor Microenviroment Unit

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54355-2

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