BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia

Sordo-Bahamonde, Christian; Lorenzo-Herrero, Seila; Martínez-Pérez, Alejandra; Gonzalez-Rodriguez, Ana P.; Payer, Ángel R.; González García, Esther; Aguilar-García, Candelaria; González-Rodríguez, Sara; López-Soto, Alejandro; García-Torre, Alejandra; Gonzalez, Segundo

BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia

Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM ax...

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Autores:	Sordo-Bahamonde, Christian, Lorenzo-Herrero, Seila, Martínez-Pérez, Alejandra, Gonzalez-Rodriguez, Ana P., Payer, Ángel R., González García, Esther, Aguilar-García, Candelaria, González-Rodríguez, Sara, López-Soto, Alejandro, García-Torre, Alejandra, Gonzalez, Segundo
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2023
País:	España
Institución:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:10230/70232
Acceso en línea:	http://hdl.handle.net/10230/70232 http://dx.doi.org/10.1007/s00262-023-03435-1
Access Level:	acceso abierto
Palabra clave:	CLL Leukemia T cell BTLA HVEM Checkpoint

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spelling	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemiaSordo-Bahamonde, ChristianLorenzo-Herrero, SeilaMartínez-Pérez, AlejandraGonzalez-Rodriguez, Ana P.Payer, Ángel R.González García, EstherAguilar-García, CandelariaGonzález-Rodríguez, SaraLópez-Soto, AlejandroGarcía-Torre, AlejandraGonzalez, SegundoCLLLeukemiaT cellBTLAHVEMCheckpointPatients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL.Nature Research202520252023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/70232http://dx.doi.org/10.1007/s00262-023-03435-1http://hdl.handle.net/10230/70232reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCancer Immunology, Immunotherapy. 2023 Jul;72(7):2529-39This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/702322026-05-29T05:05:01Z
dc.title.none.fl_str_mv	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
title	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
spellingShingle	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia Sordo-Bahamonde, Christian CLL Leukemia T cell BTLA HVEM Checkpoint
title_short	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
title_full	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
title_fullStr	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
title_full_unstemmed	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
title_sort	BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia
dc.creator.none.fl_str_mv	Sordo-Bahamonde, Christian Lorenzo-Herrero, Seila Martínez-Pérez, Alejandra Gonzalez-Rodriguez, Ana P. Payer, Ángel R. González García, Esther Aguilar-García, Candelaria González-Rodríguez, Sara López-Soto, Alejandro García-Torre, Alejandra Gonzalez, Segundo
author	Sordo-Bahamonde, Christian
author_facet	Sordo-Bahamonde, Christian Lorenzo-Herrero, Seila Martínez-Pérez, Alejandra Gonzalez-Rodriguez, Ana P. Payer, Ángel R. González García, Esther Aguilar-García, Candelaria González-Rodríguez, Sara López-Soto, Alejandro García-Torre, Alejandra Gonzalez, Segundo
author_role	author
author2	Lorenzo-Herrero, Seila Martínez-Pérez, Alejandra Gonzalez-Rodriguez, Ana P. Payer, Ángel R. González García, Esther Aguilar-García, Candelaria González-Rodríguez, Sara López-Soto, Alejandro García-Torre, Alejandra Gonzalez, Segundo
author2_role	author author author author author author author author author author
dc.subject.none.fl_str_mv	CLL Leukemia T cell BTLA HVEM Checkpoint
topic	CLL Leukemia T cell BTLA HVEM Checkpoint
description	Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL.
publishDate	2023
dc.date.none.fl_str_mv	2023 2025 2025
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10230/70232 http://dx.doi.org/10.1007/s00262-023-03435-1 http://hdl.handle.net/10230/70232
url	http://hdl.handle.net/10230/70232 http://dx.doi.org/10.1007/s00262-023-03435-1
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Cancer Immunology, Immunotherapy. 2023 Jul;72(7):2529-39
dc.rights.none.fl_str_mv	http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf application/pdf
dc.publisher.none.fl_str_mv	Nature Research
publisher.none.fl_str_mv	Nature Research
dc.source.none.fl_str_mv	reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia

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