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Nature. 2017 May 4;545(7652):98-102. doi: 10.1038/nature22311. Epub 2017 Apr 26.

Tumour ischaemia by interferon-γ resembles physiological blood vessel regression.

Author information

1
Institute of Immunology, Charité Campus Buch, 13125 Berlin, Germany.
2
Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
3
Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA.
4
Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA.
5
Berlin Institute of Health, 10117 Berlin, Germany.
6
Charité - Universitätsmedizin, 10117 Berlin, Germany.
7
Institute of Immunology, University Clinics Ulm, 89081 Ulm, Germany.
8
Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
9
Institute for Medical Microbiology, University of Marburg, 35032 Marburg, Germany.
10
Beckman Research Institute at the Comprehensive Cancer Center City of Hope, Los Angeles, California 91010-3000, USA.
11
DZHK (German Center for Cardiovascular Research), partner site Berlin, 13347 Berlin, Germany.

Abstract

The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ-GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.

PMID:
28445461
PMCID:
PMC5567674
DOI:
10.1038/nature22311
[Indexed for MEDLINE]
Free PMC Article

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