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...
| Authors: | ; ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2023 |
| Country: | España |
| Institution: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repository: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/70232 |
| Online Access: | http://hdl.handle.net/10230/70232 http://dx.doi.org/10.1007/s00262-023-03435-1 |
| Access Level: | Open access |
| Keyword: | CLL Leukemia T cell BTLA HVEM Checkpoint |
| _version_ | 1878735784875393025 |
|---|---|
| author | Sordo-Bahamonde, Christian |
| 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 |
| author_browse | Aguilar-García, Candelaria García-Torre, Alejandra Gonzalez, Segundo Gonzalez-Rodriguez, Ana P. González García, Esther González-Rodríguez, Sara Lorenzo-Herrero, Seila López-Soto, Alejandro Martínez-Pérez, Alejandra Payer, Ángel R. 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 |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_8360e4ecc47e00a019958f23f42b756f |
| institution | 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) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:10230/70232 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| publisher | Nature Research |
| publisherStr | Nature Research |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | 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 CLL Leukemia T cell BTLA HVEM Checkpoint 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. Nature Research http://hdl.handle.net/10230/70232 http://dx.doi.org/10.1007/s00262-023-03435-1 |
| 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 |
| status_str | publishedVersion |
| title | 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_short | 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 |
| topic | CLL Leukemia T cell BTLA HVEM Checkpoint |
| topic_facet | CLL Leukemia T cell BTLA HVEM Checkpoint |
| url | http://hdl.handle.net/10230/70232 http://dx.doi.org/10.1007/s00262-023-03435-1 |