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

June 8, 2017

Highlights:
    • This study shows 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 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.
    • Conclusion: Effective immunotherapy is a consequence of successful homing of T cells in response to local complement activation, which disrupts the tumor endothelial barrier.
Author and source information

Authors: 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.
Reference: Oncoimmunology. 2017 Jun 8;6(9):e1326442. doi: 10.1080/2162402X.2017.1326442. eCollection 2017.
Source: www.ncbi.nlm.nih.gov

 

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