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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI184036

Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity

Eleonora Russo,1 Chiara D'Aquino,1 Chiara Di Censo,1 Mattia Laffranchi,1 Luana Tomaipitinca,1 Valerio Licursi,2 Stefano Garofalo,3 Johann Promeuschel,1 Giovanna Peruzzi,4 Francesca Sozio,5 Anna Kaffke,6 Cecilia Garlanda,7 Ulf Panzer,6 Cristina Limatola,3 Christian A. J. Vosshenrich,8 Silvano Sozzani,1 Giuseppe Sciumè,1 Angela Santoni,1 and Giovanni Bernardini1

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Russo, E. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by D'Aquino, C. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

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1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Laffranchi, M. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Tomaipitinca, L. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Licursi, V. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Garofalo, S. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Promeuschel, J. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Peruzzi, G. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Sozio, F. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Kaffke, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Garlanda, C. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Panzer, U. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Limatola, C. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Vosshenrich, C. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Sozzani, S. in: JCI | PubMed | Google Scholar |

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Sciumè, G. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Santoni, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur, Sapienza University of Rome, Rome, Italy

2Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), Rome, Italy

3Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

4Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy

5Department of Surgery, Sapienza University of Rome, Rome, Italy

6III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7Department of Biomedical Sciences, Humanitas University, Milan, Italy

8Innate Immunity Unit, Institut Pasteur, Université Paris Cité, Paris, France

Find articles by Bernardini, G. in: JCI | PubMed | Google Scholar

Published April 1, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI184036.
Copyright © 2025, Russo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 1, 2025 - Version history
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Abstract

The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics remain unclear. Herein, we investigated the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+NK cell population within the liver metastasis (LM) environment of colorectal cancer (CRC). We show that CD49a+NK cells had the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promoted CD49a+NK cell accumulation and persistence in metastasis where NK cells co-localize with macrophages in CXCL9 and CXCL10 rich areas. By mining a published scRNA-seq dataset of a cohort of treatment-naïve CRC patients, we confirmed the accumulation of CXCR3+NK cells in metastatic samples. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages impaired CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in LM. Conversely, CXCR3neg NK cells maintained a CD49a- phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+NK cell accumulation was impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in CRC LM.

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graphical abstract
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View Supplemental information related to data set analysis from Liu et al Cancer Cell 2022

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  • Version 1 (April 1, 2025): In-Press Preview
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