Tumour ischaemia by interferon-γ resembles physiological blood vessel regression

Abstract

Interferon-γ acts on tumour endothelial cells to drive vascular regression, inducing ischaemia that leads to tumour collapse. Anti-tumour immune cells can elicit effects in tumours and stroma, but also in the blood vessels. Many of these effects are driven by secreted IFNγ, a cytokine with important functions in immunity. Using a combination of genetically engineered mouse models, the authors demonstrate that the effects of IFNγ on the vasculature is an important mediator of tumour clearance by the immune system. IFNγ-mediated tumour vascular remodelling resembles physiological processes, for example non-apoptotic blood vessel regression during wound healing, and induces early ischaemia that impairs the growth of tumour cells. 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 models1. Although IFNγ can impede tumour growth by acting directly on cancer cells2,3, it must also act on the tumour stroma for effective rejection of large, established tumours4,5. 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 arteries6,7,8. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.

Cite this article

Kammertoens, T., Friese, C., Arina, A. et al. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature 545, 98–102 (2017). https://doi.org/10.1038/nature22311

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