Abstract
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
Joanna Mikulak, Domenico Supino, Paolo Marzano, Sara Terzoli, Roberta Carriero, Valentina Cazzetta, Rocco Piazza, Elena Bruni, Paolo Kunderfranco, Alessia Donato, Sarah Natalia Mapelli, Roberto Garuti, Silvia Carnevale, Francesco Scavello, Elena Magrini, Jelena Zeleznjak, Clelia Peano, Matteo Donadon, Guido Costa, Guido Torzilli, Alberto Mantovani, Cecilia Garlanda, Domenico Mavilio
Graphical abstract
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)