The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-gamma (IFNgamma) is critical in most of the analysed models. Although IFNgamma 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 IFNgamma and by which mechanism IFNgamma contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNgamma induction and an IFNgamma-GFP fusion protein in large, vascularized tumours growing in mice that express the IFNgamma receptor exclusively in defined cell types. Responsiveness to IFNgamma by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNgamma-induced tumour regression, whereas responsiveness of endothelial cells to IFNgamma was necessary and sufficient. Intravital microscopy revealed IFNgamma-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 IFNgamma-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNgamma-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.
Author Info: (1) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (2) Institute of Immunology, Charite Cam
Author Info: (1) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (2) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck 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) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (6) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (7) Berlin Institute of Health, 10117 Berlin, Germany. Charite - Universitatsmedizin, 10117 Berlin, Germany. (8) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (9) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (10) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (11) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (12) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (13) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. Berlin Institute of Health, 10117 Berlin, Germany. (14) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. (15) Institute of Immunology, University Clinics Ulm, 89081 Ulm, Germany. (16) Institute of Ophthalmology, University College London, London EC1V 9EL, UK. (17) Institute for Medical Microbiology, University of Marburg, 35032 Marburg, Germany. (18) Beckman Research Institute at the Comprehensive Cancer Center City of Hope, Los Angeles, California 91010-3000, USA. (19) Beckman Research Institute at the Comprehensive Cancer Center City of Hope, Los Angeles, California 91010-3000, USA. (20) Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois 60637, USA. (21) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. Berlin Institute of Health, 10117 Berlin, Germany. (22) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. Charite - Universitatsmedizin, 10117 Berlin, Germany. DZHK (German Center for Cardiovascular Research), partner site Berlin, 13347 Berlin, Germany. (23) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. Berlin Institute of Health, 10117 Berlin, Germany. DZHK (German Center for Cardiovascular Research), partner site Berlin, 13347 Berlin, Germany. (24) Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. Berlin Institute of Health, 10117 Berlin, Germany. (25) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA. Berlin Institute of Health, 10117 Berlin, Germany. (26) Institute of Immunology, Charite Campus Buch, 13125 Berlin, Germany. Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. Berlin Institute of Health, 10117 Berlin, Germany.
