Tumour ischaemia by interferon-γ resembles physiological blood vessel regression


  • T. Kammertoens
  • C. Friese
  • A. Arina
  • C. Idel
  • D. Briesemeister
  • M. Rothe
  • A. Ivanov
  • A. Szymborska
  • G. Patone
  • S. Kunz
  • D. Sommermeyer
  • B. Engels
  • M. Leisegang
  • A. Textor
  • H.J. Fehling
  • M. Fruttiger
  • M. Lohoff
  • A. Herrmann
  • H. Yu
  • R. Weichselbaum
  • W. Uckert
  • N. Hübner
  • H. Gerhardt
  • D. Beule
  • H. Schreiber
  • T. Blankenstein


  • Nature


  • Nature 545 (7652): 98-102


  • The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-{gamma} (IFN{gamma}) is critical in most of the analysed models. Although IFN{gamma} 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 IFN{gamma} and by which mechanism IFN{gamma} contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFN{gamma} induction and an IFN{gamma}-GFP fusion protein in large, vascularized tumours growing in mice that express the IFN{gamma} receptor exclusively in defined cell types. Responsiveness to IFN{gamma} by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFN{gamma}-induced tumour regression, whereas responsiveness of endothelial cells to IFN{gamma} was necessary and sufficient. Intravital microscopy revealed IFN{gamma}-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 IFN{gamma}-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFN{gamma}-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.