Neutrophil Conversion to a Tumor-Killing Phenotype Underpins Effective Microbial Therapy.

Autor:	Yam AO; Garvan Institute of Medical Research, Sydney, New South Wales, Australia.; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia.; The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, New South Wales, Australia., Bailey J; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Lin F; Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Jakovija A; Garvan Institute of Medical Research, Sydney, New South Wales, Australia.; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia., Youlten SE; Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Counoupas C; Discipline of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia., Gunzer M; Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany.; Leibniz-Institut für Analytische Wissenschaften - ISAS-e.V., Dortmund, Germany., Bald T; Institute of Experimental Oncology University Hospital Bonn Venusberg-Campus 1, Bonn, Germany., Woodruff TM; School of Biomedical Sciences, The University of Queensland, Research Road, St Lucia, Brisbane, Queensland, Australia., Triccas JA; Discipline of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia., Goldstein LD; Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Gallego-Ortega D; Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.; School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Ultimo, New South Wales, Australia., Grey ST; Garvan Institute of Medical Research, Sydney, New South Wales, Australia.; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales Sydney, Kensington, New South Wales, Australia., Chtanova T; Garvan Institute of Medical Research, Sydney, New South Wales, Australia.; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales Sydney, Kensington, New South Wales, Australia.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Apr 14; Vol. 83 (8), pp. 1315-1328.
DOI:	10.1158/0008-5472.CAN-21-4025
Abstrakt:	The inflammatory microenvironment of solid tumors creates a protumorigenic milieu that resembles chronic inflammation akin to a subverted wound healing response. Here, we investigated the effect of converting the tumor microenvironment from a chronically inflamed state to one of acute microbial inflammation by injecting microbial bioparticles directly into tumors. Intratumoral microbial bioparticle injection led to rapid and dramatic changes in the tumor immune composition, the most striking of which was a substantial increase in the presence of activated neutrophils. In situ photoconversion and intravital microscopy indicated that tumor neutrophils transiently switched from sessile producers of VEGF to highly motile neutrophils that clustered to make neutrophil-rich domains in the tumor. The neutrophil clusters remodeled tumor tissue and repressed tumor growth. Single-cell transcriptional analysis of microbe-stimulated neutrophils showed a profound shift in gene expression towards heightened activation and antimicrobial effector function. Microbe-activated neutrophils also upregulated chemokines known to regulate neutrophil and CD8+ T-cell recruitment. Microbial therapy also boosted CD8+ T-cell function and enhanced the therapeutic benefit of checkpoint inhibitor therapy in tumor-bearing mice and provided protection in a model of tumor recurrence. These data indicate that one of the major effector mechanisms of microbial therapy is the conversion of tumor neutrophils from a wound healing to an acutely activated cytotoxic phenotype, highlighting a rationale for broader deployment of microbial therapy in the treatment of solid cancers. Significance: Intratumoral injection of microbial bioparticles stimulates neutrophil antitumor functions, suggesting pathways for optimizing efficacy of microbial therapies and paving the way for their broader utilization in the clinic. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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