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Oncoimmunology. 2017 Jun 8;6(9):e1326442. doi: 10.1080/2162402X.2017.1326442. eCollection 2017.

Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy.

Author information

1
Ovarian Cancer Research Center and Department of Obstetrics and Gynecology, University of Pennsylvania; Philadelphia, PA, USA.
2
Department of Experimental Medicine and Biochemical Science, University of Perugia, Perugia, Italy.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Ludwig Institute of Cancer Research and Department of Oncology, University of Lausanne, Switzerland.
5
Internal Medicine Division of Hematology Oncology Obstetrics and Gynecology Division of Gynecologic Oncology, University of Michigan, MI, USA.
6
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.

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

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