Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies
| Title: | Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies |
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| Authors: | Ángel Ramírez-Fernández, Óscar Aguilar-Sopeña, Laura Díez-Alonso, Alejandro Segura-Tudela, Carmen Domínguez-Alonso, Pedro Roda-Navarro, Luis Álvarez-Vallina, Belén Blanco |
| Source: | OncoImmunology, Vol 11, Iss 1 (2022) |
| Publisher Information: | Taylor & Francis Group, 2022. |
| Publication Year: | 2022 |
| Collection: | LCC:Immunologic diseases. Allergy LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: | CD19+ B cell malignancies, T cell-redirecting strategies, STAb, BiTE, CAR, leukemia relapse, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: | Cancer immunotherapy strategies based on the endogenous secretion of T cell-redirecting bispecific antibodies by engineered T lymphocytes (STAb-T) are emerging as alternative or complementary approaches to those based on chimeric antigen receptors (CAR-T). The antitumor efficacy of bispecific anti-CD19 × anti-CD3 (CD19×CD3) T cell engager (BiTE)-secreting STAb-T cells has been demonstrated in several mouse models of B-cell acute leukemia. Here, we have investigated the spatial topology and downstream signaling of the artificial immunological synapses (IS) that are formed by CAR-T or STAb-T cells. Upon interaction with CD19-positive target cells, STAb-T cells form IS with structure and signal transduction, which more closely resemble those of physiological cognate IS, compared to IS formed by CAR-T cells expressing a second-generation CAR bearing the same CD19-single-chain variable fragment. Importantly, while CD3 is maintained at detectable levels on the surface of STAb-T cells, indicating sustained activation mediated by the secreted BiTE, the anti-CD19 CAR was rapidly downmodulated, which correlated with a more transient downstream signaling. Furthermore, CAR-T cells, but not STAb-T cells, provoke an acute loss of CD19 in target cells. Such differences might represent advantages of the STAb-T strategy over the CAR-T approach and should be carefully considered in order to develop more effective and safer treatments for hematological malignancies. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2162402X 2162-402X |
| Relation: | https://doaj.org/toc/2162-402X |
| DOI: | 10.1080/2162402X.2022.2054106 |
| Access URL: | https://doaj.org/article/a738330a8b26462fa166a9c5d196ff70 |
| Accession Number: | edsdoj.738330a8b26462fa166a9c5d196ff70 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2162402X |
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| DOI: | 10.1080/2162402X.2022.2054106 |
| Published in: | OncoImmunology |
| Language: | English |