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Updated: Jun 6, 2025
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer
Federica Portale1, Roberta Carriero2, Marta Iovino1
1IRCCS Humanitas Research Hospital, Tumor Microenviroment Unit, 20089, Via Manzoni 56, Rozzano, Milan, Italy.
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.
Insights
This study reveals that autophagy regulates Natural Killer (NK) cell anti-tumor function. Activating autophagy enhances NK cell activity, offering a new strategy to improve cancer immunotherapies.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Metabolism
Background:
- Natural Killer (NK) cells possess tumor-killing capabilities, but cancer often impairs their function, limiting the efficacy of cell-based therapies in solid tumors.
- Understanding how cancers suppress NK cell activity is crucial for developing effective immune-therapies.
- Autophagy, a cellular degradation process, has emerged as a potential regulator of immune cell function.
Purpose of the Study:
- To investigate the role of autophagy in regulating NK cell anti-tumor function in the context of cancer.
- To identify the molecular mechanisms by which cancer impairs NK cell activity.
- To explore autophagy modulation as a therapeutic strategy to enhance NK cell-based cancer immunotherapies.
Main Methods:
- Differential gene expression analysis (scRNA-seq) of tumor-infiltrating versus non-tumor NK cells from prostate cancer patients.
- Flow cytometry validation in human patients and murine cancer models.
- Investigation of the mechanistic link between cancer exposure, autophagy, mitochondrial function, and NK cell effector functions.
- Assessment of the impact of inhibiting or activating autophagy on NK cell activity and tumor control.
Main Results:
- Deregulation of the autophagic pathway was observed in tumor-infiltrating NK cells compared to non-tumor NK cells.
- Exposure to cancer deregulated autophagy, decreased mitochondrial polarization, and impaired NK cell effector functions.
- CCAAT enhancer binding protein beta (C/EBPβ), regulated by CXCL12-CXCR4, was identified as a key regulator of NK cell metabolism.
- Inhibition of CXCR4 and C/EBPβ restored NK cell fitness, while autophagy activation improved NK cell effector and cytotoxic functions, leading to tumor control.
Conclusions:
- Autophagy acts as an intracellular checkpoint controlling NK cell anti-tumor functions.
- Targeting autophagy presents a promising approach to enhance the efficacy of NK cell-based immunotherapies for cancer treatment.
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