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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\u2009+\u2009and CD8\u2009+\u2009T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4\u2009+\u2009T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-\u03b3 production ex vivo, whereas BTLA\/HVEM binding disruption enhanced IFN-\u03b3\u2009+\u2009CD8\u2009+\u2009T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3\/anti-CD19 antibody promoted CD8\u2009+\u2009T 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.<\/jats:p>","DOI":"10.1007\/s00262-023-03435-1","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T20:31:33Z","timestamp":1681245093000},"page":"2529-2539","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia"],"prefix":"10.1007","volume":"72","author":[{"given":"Christian","family":"Sordo-Bahamonde","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seila","family":"Lorenzo-Herrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Mart\u00ednez-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P.","family":"Gonzalez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel R.","family":"Payer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Gonz\u00e1lez-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candelaria","family":"Aguilar-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gonz\u00e1lez-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"L\u00f3pez-Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Garc\u00eda-Torre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Segundo","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"3435_CR1","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1038\/s41571-019-0239-8","volume":"16","author":"F Bosch","year":"2019","unstructured":"Bosch F, Dalla-Favera R (2019) Chronic lymphocytic leukaemia: from genetics to treatment. 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