Vascular normalization in Rgs5-deficient tumours promotes immune destruction

• Published in: Nature 2008-05, Vol.453 (7193), p.410-414
• Main Authors: Hamzah, Juliana, Jugold, Manfred, Kiessling, Fabian, Rigby, Paul, Manzur, Mitali, Marti, Hugo H., Rabie, Tamer, Kaden, Sylvia, Gröne, Hermann-Josef, Hämmerling, Günter J., Arnold, Bernd, Ganss, Ruth
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Capillary Permeability; Cardiovascular tumors; Cell Hypoxia - physiology; Cells; Drugs; Experimental tumors, general aspects; Female; Histology; Humanities and Social Sciences; Hypoxia; Immune system; Immunization; letter; Lymphocytes; Male; Management; Medical sciences; Mice; multidisciplinary; Neovascularization, Pathologic - prevention & control; Oxygen - metabolism; Pancreatic Neoplasms - blood supply; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Permeability; Physiological aspects; RGS Proteins - deficiency; RGS Proteins - genetics; RGS Proteins - metabolism; Rodents; Science; Science (multidisciplinary); Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature06868

Anticancer immunotherapy: It's in the blood RGS5, a signalling protein that regulates the activity of G proteins, is shown to be an important regulator of the tumour vasculature. Deletion of Rgs5 leads to normalization of blood vessels of tumours, making them less leaky and improving their coverage with pericytes. As a consequence, more immune cells that can target the tumour cells actually reach the tumour, which enhances the survival of tumour-bearing mice. Thus RGS5 signalling might be a target for anticancer therapy, in particular in combination with approaches that enhance an antitumour immune response. RGS5, a signalling protein that regulates the activity of G proteins, is shown to be an important regulator of the tumour vasculature. Deletion of RGS5 leads to normalization of blood vessels of tumours, making them less leady and improving their coverage with pericytes. As a consequence, more immune cells that can target the tumour cells reach the tumour, which enhances the survival of tumour-bearing mice. The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture 1 . Constant vessel remodelling leads to spontaneous haemorrhages 2 and increased interstitial fluid pressure in the tumour environment 3 , 4 . Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma 2 , 5 , 6 . The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 ( Rgs5 ) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.