Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy.
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State: Public
Version: Final published version
State: Public
Version: Final published version
Serval ID
serval:BIB_69B217E99597
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy.
Journal
Oncoimmunology
ISSN
2162-4011 (Print)
ISSN-L
2162-4011
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
6
Number
9
Pages
e1326442
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Abstract
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.
Keywords
C5a, Cancer, complement, endothelium, immunotherapy
Pubmed
Web of science
Open Access
Yes
Create date
09/10/2017 10:32
Last modification date
20/08/2019 15:24