Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-09-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1326442 |
| _version_ | 1818204669170679808 |
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| author | Andrea Facciabene Francesco De Sanctis Stefano Pierini Edimara S. Reis Klara Balint John Facciponte Jens Rueter Masahiro Kagabu Paola Magotti Evripidis Lanitis Robert A. DeAngelis Ronald J. Buckanovich Wenchao C. Song John D. Lambris George Coukos |
| author_facet | Andrea Facciabene Francesco De Sanctis Stefano Pierini Edimara S. Reis Klara Balint John Facciponte Jens Rueter Masahiro Kagabu Paola Magotti Evripidis Lanitis Robert A. DeAngelis Ronald J. Buckanovich Wenchao C. Song John D. Lambris George Coukos |
| author_sort | Andrea Facciabene |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T03:44:54Z |
| format | Article |
| id | doaj.art-481efa6cbcba4de396fa76f797310012 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-12T03:44:54Z |
| publishDate | 2017-09-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-481efa6cbcba4de396fa76f7973100122022-12-22T00:39:35ZengTaylor & Francis GroupOncoImmunology2162-402X2017-09-016910.1080/2162402X.2017.13264421326442Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapyAndrea Facciabene0Francesco De Sanctis1Stefano Pierini2Edimara S. Reis3Klara Balint4John Facciponte5Jens Rueter6Masahiro Kagabu7Paola Magotti8Evripidis Lanitis9Robert A. DeAngelis10Ronald J. Buckanovich11Wenchao C. Song12John D. Lambris13George Coukos14University of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of MichiganUniversity of PennsylvaniaUniversity of PennsylvaniaUniversity of PennsylvaniaCancer 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.http://dx.doi.org/10.1080/2162402X.2017.1326442cancercomplementc5aendotheliumimmunotherapy |
| spellingShingle | Andrea Facciabene Francesco De Sanctis Stefano Pierini Edimara S. Reis Klara Balint John Facciponte Jens Rueter Masahiro Kagabu Paola Magotti Evripidis Lanitis Robert A. DeAngelis Ronald J. Buckanovich Wenchao C. Song John D. Lambris George Coukos Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy OncoImmunology cancer complement c5a endothelium immunotherapy |
| title | Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy |
| title_full | Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy |
| title_fullStr | Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy |
| title_full_unstemmed | Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy |
| title_short | Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy |
| title_sort | local endothelial complement activation reverses endothelial quiescence enabling t cell homing and tumor control during t cell immunotherapy |
| topic | cancer complement c5a endothelium immunotherapy |
| url | http://dx.doi.org/10.1080/2162402X.2017.1326442 |
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