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2017 ; 6
(9
): e1326442
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English Wikipedia
Local endothelial complement activation reverses endothelial quiescence, enabling
t-cell homing, and tumor control during t-cell immunotherapy
#MMPMID28932632
Facciabene A
; De Sanctis F
; Pierini S
; Reis ES
; Balint K
; Facciponte J
; Rueter J
; Kagabu M
; Magotti P
; Lanitis E
; DeAngelis RA
; Buckanovich RJ
; Song WC
; Lambris JD
; Coukos G
Oncoimmunology
2017[]; 6
(9
): e1326442
PMID28932632
show ga
Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The
endothelium constitutes a barrier between the tumor and effector T cells, and the
ability to manipulate local vascular permeability could be translated into
effective immunotherapy. Here, we show that in the context of adoptive T cell
therapy, antitumor T cells, delivered at high enough doses, can overcome the
endothelial barrier and infiltrate tumors, a process that requires local
production of C3, complement activation on tumor endothelium and release of C5a.
C5a, in turn, acts on endothelial cells promoting the upregulation of adhesion
molecules and T-cell homing. Genetic deletion of C3 or the C5a receptor 1
(C5aR1), and pharmacological blockade of C5aR1, impaired the ability of T cells
to overcome the endothelial barrier, infiltrate tumors, and control tumor
progression in vivo, while genetic chimera mice demonstrated that C3 and C5aR1
expression by tumor stroma, and not leukocytes, governs T cell homing, acting on
the local endothelium. In vitro, endothelial C3 and C5a expressions were required
for endothelial activation by type 1 cytokines. Our data indicate that effective
immunotherapy is a consequence of successful homing of T cells in response to
local complement activation, which disrupts the tumor endothelial barrier.