C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer
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.
Authors
- Marta Iovino (ORCID: https://orcid.org/0000-0002-1460-8899)
- Giulia Marelli (ORCID: https://orcid.org/0000-0002-5688-1009)
- Francesco Cecconi (ORCID: https://orcid.org/0000-0002-5614-4359)
- Javier Cibella (ORCID: https://orcid.org/0000-0002-2895-8152)
- Massimo Lazzeri (ORCID: https://orcid.org/0000-0002-4411-3715)
- Alessandro Corbelli (ORCID: https://orcid.org/0000-0001-8545-8050)
- Diletta Di Mitri (ORCID: https://orcid.org/0000-0002-9626-4259)
- Enrico Lugli (ORCID: https://orcid.org/0000-0002-1964-7678)
- Paolo Casale (ORCID: https://orcid.org/0000-0002-7899-5736)
- Fabio Fiordaliso (ORCID: https://orcid.org/0000-0002-0172-4030)
- Torsten Tonn (ORCID: https://orcid.org/0000-0001-9580-2193)
- Piergiuseppe Colombo (ORCID: https://orcid.org/0000-0002-6161-6138)
- Nicolò Morina (ORCID: https://orcid.org/0000-0003-4070-1410)
- Matteo Bordi (ORCID: https://orcid.org/0000-0001-8207-8546)
- Jiří Eitler (ORCID: https://orcid.org/0000-0002-3175-2438)
- Chiara Camisaschi (ORCID: https://orcid.org/0000-0002-5205-919X)
- Federica Portale (ORCID: https://orcid.org/0000-0002-4730-5931)
- Monica Dambra (ORCID: https://orcid.org/0000-0003-3075-4279)
- Roberta Carriero (ORCID: https://orcid.org/0000-0001-8619-6152)
- Sergio Marchini (ORCID: https://orcid.org/0000-0003-1783-7651)
- Elena Magrini (ORCID: https://orcid.org/0000-0003-1507-2325)
- Marta Pandini (ORCID: https://orcid.org/0000-0002-6235-3181)
- Gianluca Basso (ORCID: https://orcid.org/0000-0002-8430-4727)
- Gabriele De Simone (ORCID: https://orcid.org/0000-0001-6103-4376)
- Anna Garbin
- Wiebke Rackwitz
- Greta Meregalli
- Paolo Kunderfranco (ORCID: https://orcid.org/0000-0003-3636-3391)
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Humanitas University (IT)
- Mario Negri Institute for Pharmacological Research (IT)
- German Red Cross (DE)
- Agostino Gemelli University Polyclinic (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University Hospital Carl Gustav Carus (DE)
- IRCCS Humanitas Research Hospital (IT)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1038/s41467-024-54355-2
- Citations
- 17
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 4.09
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Ministero della Salute
- Westfälische Wilhelms-Universität Münster
- Associazione Italiana per la Ricerca sul Cancro