Tissue-specific antitumor NK cell subsets identified in colorectal cancer liver metastases express candidate therapeutic targets
Liver metastases are relatively resistant to checkpoint blockade immunotherapy. The hepatic tissue has distinctive features including high numbers of NK cells. It was therefore important to conduct in-depth single-cell analysis of NK cells in colorectal cancer liver metastases (CRLMs) with an effort to dissect their diversity and to identify candidate therapeutic targets. By combining unbiased single-cell transcriptomic with multiparametric flow cytometry analysis, we identified an abundant family of intrahepatic CD56bright NK cells in CRLMs endowed with antitumor functions resulting from specific transcriptional liver programs. Intrahepatic CD56bright and CD56dim NK lymphocytes expressed unique transcription factors (IRF8, TOX2), a high level of chemokines, and targetable immune checkpoints, including CXCR4 and the IL-1 receptor family member IL-1R8. CXCR4 pharmacological blocking and an anti-IL-1R8 mAb enhanced the effector function of CRLM NK cells. Targeting the diversity of liver NK cells and their distinct immune checkpoint repertoires is key to optimize the current immune therapy protocols in CRLM.
Authors
- Francesco Scavello (ORCID: https://orcid.org/0000-0002-0297-0946)
- Sara Terzoli (ORCID: https://orcid.org/0000-0003-2650-7195)
- Elena Bruni (ORCID: https://orcid.org/0000-0003-4714-8275)
- Valentina Cazzetta (ORCID: https://orcid.org/0000-0001-7183-2793)
- Domenico Mavilio (ORCID: https://orcid.org/0000-0001-6147-0952)
- Joanna Mikulak (ORCID: https://orcid.org/0000-0001-8310-9543)
- Sarah N. Mapelli (ORCID: https://orcid.org/0000-0002-0129-2055)
- Jelena Železnjak (ORCID: https://orcid.org/0000-0001-6619-3675)
- Cecília Garlanda (ORCID: https://orcid.org/0000-0002-1510-7703)
- Alberto Mantovani (ORCID: https://orcid.org/0000-0001-5578-236X)
- Rocco Piazza (ORCID: https://orcid.org/0000-0003-4198-9620)
- Guido Torzilli (ORCID: https://orcid.org/0000-0001-5798-5021)
- Silvia Carnevale (ORCID: https://orcid.org/0000-0002-9176-5636)
- Roberta Carriero (ORCID: https://orcid.org/0000-0001-8619-6152)
- Guido Costa (ORCID: https://orcid.org/0000-0003-3986-8790)
- Elena Magrini (ORCID: https://orcid.org/0000-0003-1507-2325)
- Rita Garuti (ORCID: https://orcid.org/0009-0008-8551-8832)
- Paolo Marzano (ORCID: https://orcid.org/0000-0002-5614-4033)
- Clelia Peano (ORCID: https://orcid.org/0000-0001-7055-3629)
- Domenico Supino (ORCID: https://orcid.org/0000-0001-9690-1791)
- Alessia Donato
- Matteo Donadon (ORCID: https://orcid.org/0000-0003-0296-7648)
- Paolo Kunderfranco (ORCID: https://orcid.org/0000-0003-3636-3391)
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Humanitas University (IT)
- University of Rijeka (HR)
- Queen Mary University of London (GB)
- University of Milan (IT)
- Scientific Research Institute of Experimental and Clinical Medicine (RU)
- Human Technopole (IT)
- Institute of Clinical and Experimental Medicine (CZ)
- William Harvey Research Institute (GB)
- National Research Council (IT)
- IRCCS Humanitas Research Hospital (IT)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1172/jci190778
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80