Vascular normalization in Rgs5-deficient tumours promotes immune destruction.
The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. 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. 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.
Hamzah
Juliana
J
Western Australian Institute for Medical Research, UWA Centre for Medical Research, Perth, Western Australia 6000, Australia.
Jugold
Manfred
M
Kiessling
Fabian
F
Rigby
Paul
P
Manzur
Mitali
M
Marti
Hugo H
HH
Rabie
Tamer
T
Kaden
Sylvia
S
Gröne
Hermann-Josef
HJ
Hämmerling
Günter J
GJ
Arnold
Bernd
B
Ganss
Ruth
R
D000818:Animals; D002199:Capillary Permeability; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010100:Oxygen / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020710:RGS Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D020710:RGS Proteins; C105346:Rgs5 protein, mouse; D010100:Oxygen