Intrahepatic CD69 + Vδ1 T cells re-circulate in the blood of patients with metastatic colorectal cancer and limit tumor progression.

Autor:	Bruni E; Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy., Cimino MM; Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Donadon M; Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Health Science, Università del Piemonte Orientale, Novara, Italy., Carriero R; Bioinformatics Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Terzoli S; Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy., Piazza R; Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy., Ravens S; Institute of Immunology, Hannover Medical School (MHH), Hannover, Germany., Prinz I; Institute of Immunology, Hannover Medical School (MHH), Hannover, Germany.; Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Cazzetta V; Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy., Marzano P; Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy., Kunderfranco P; Bioinformatics Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Peano C; Institute of Biomedical Technologie, CNR Milan, Human Technopole, Milan, Italy., Soldani C; Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Franceschini B; Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Colombo FS; Humanitas Flow Cytometry Core, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Garlanda C; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy., Mantovani A; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; The William Harvey Research Institute, Queen Mary University of London, London, UK., Torzilli G; Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy., Mikulak J; Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy., Mavilio D; Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy domenico.mavilio@humanitas.it.; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jul; Vol. 10 (7).
DOI:	10.1136/jitc-2022-004579
Abstrakt:	Background: More than 50% of all patients with colorectal cancer (CRC) develop liver metastases (CLM), a clinical condition characterized by poor prognosis and lack of reliable prognostic markers. Vδ1 cells are a subset of tissue-resident gamma delta (γδ) T lymphocytes endowed with a broad array of antitumor functions and showing a natural high tropism for the liver. However, little is known about their impact in the clinical outcomes of CLM. Methods: We isolated human γδ T cells from peripheral blood (PB) and peritumoral (PT) tissue of 93 patients undergone surgical procedures to remove CLM. The phenotype of freshly purified γδ T cells was assessed by multiparametric flow cytometry, the transcriptional profiles by single cell RNA-sequencing, the functional annotations by Gene Ontology enrichment analyses and the clonotype by γδ T cell receptor (TCR)-sequencing. Results: The microenvironment of CLM is characterized by a heterogeneous immune infiltrate comprising different subsets of γδ tumor-infiltrating lymphocytes (TILs) able to egress the liver and re-circulate in PB. Vδ1 T cells represent the largest population of γδ TILs within the PT compartment of CLM that is greatly enriched in Vδ1 T effector (T EF ) cells expressing constitutive high levels of CD69. These Vδ1 CD69 + TILs express a distinct phenotype and transcriptional signature, show high antitumor potential and correlate with better patient clinical outcomes in terms of lower numbers of liver metastatic lesions and longer overall survival (OS). Moreover, intrahepatic CD69 + Vδ1 TILs can egress CLM tissue to re-circulate in PB, where they retain a phenotype, transcriptional signature and TCR clonal repertoires resembling their liver origin. Importantly, even the increased frequencies of the CD69 + terminally differentiated (T EMRA ) Vδ1 cells in PB of patients with CLM significantly correlate with longer OS. The positive prognostic score of high frequencies of CD69 + T EMRA Vδ1 cells in PB is independent from the neoadjuvant chemotherapy and immunotherapy regimens administered to patients with CLM prior surgery. Conclusions: The enrichment of tissue-resident CD69 + Vδ1 T EMRA cells re-circulating at high frequencies in PB of patients with CLM limits tumor progression and represents a new important clinical tool to either predict the natural history of CLM or develop alternative therapeutic protocols of cellular therapies. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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