RT Journal Article
T1 Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies
A1 Ramírez Fernández, Ángel
A1 Aguilar Sopeña, Óscar
A1 Díez Alonso, Laura
A1 Segura Tudela, Alejandro
A1 Domínguez Alonso, Carmen
A1 Roda Navarro, Pedro
A1 Álvarez Vallina, Luis
A1 Blanco, Belén
AB 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.
PB Taylor and Francis
SN 2162-402X
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/120069
UL https://hdl.handle.net/20.500.14352/120069
LA eng
NO Ramírez-Fernández Á, Aguilar-Sopeña Ó, Díez-Alonso L, Segura-Tudela A, Domínguez-Alonso C, Roda-Navarro P, Álvarez-Vallina L, Blanco B. Synapse topology and downmodulation events determine the functional outcome of anti-CD19 T cell-redirecting strategies. Oncoimmunology. 2022 Mar 23;11(1):2054106. doi: 10.1080/2162402X.2022.2054106
NO European Commission
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Instituto de Salud Carlos III (España)
DS Docta Complutense
RD 7 jun 2025