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Tumour ischaemia by interferon-γ resembles physiological blood vessel regression

Kammertoens, Thomas and Friese, Christian and Arina, Ainhoa and Idel , Christian and Briesemeister, Dana and Rothe, Michael and Sommermeyer, Daniel and Engels, Boris and Leisegang, Matthias and Fehling, Hans J and Fruttiger, Marcus and Herrmann, Andreas and Yu, Hua and Weichselbaum, Ralph and Uckert, Wolfgang and Schreiber, Hans and Blankenstein, Thomas (2017) Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature, 545 (7652). pp. 98-102. ISSN 14764687

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.

Item Type: Article
Date Deposited: 19 Apr 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/28130

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