{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:33:53Z","timestamp":1785407633217,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Moroccan Ministry of Higher Education, Research, and Innovation","award":["A PPR1"],"award-info":[{"award-number":["A PPR1"]}]},{"name":"Moroccan Ministry of Higher Education, Research, and Innovation and the Digital Development Agency","award":["Al-khawarizmi"],"award-info":[{"award-number":["Al-khawarizmi"]}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["624289-PANAF-1-2020\u20131-KEPANAFMOBAF"],"award-info":[{"award-number":["624289-PANAF-1-2020\u20131-KEPANAFMOBAF"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["624289-PANAF-1-2020\u20131-KEPANAFMOBAF"],"award-info":[{"award-number":["624289-PANAF-1-2020\u20131-KEPANAFMOBAF"]}],"id":[{"id":"https:\/\/ror.org\/00k4n6c32","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Med. Sci.","Medical Sciences"],"abstract":"<jats:p>Background: Successful translation of cancer immunotherapy is underscored by the efficacy of PD-1\/PD-L1 and CTLA-4 inhibitors in the treatment of various malignancies. However, their limited efficacy in glioma indicates alternative immune escape mechanisms. We investigated B and T Lymphocyte Attenuator (BTLA), a co-inhibitory receptor structurally and functionally analogous to PD-1, to determine if it constitutes a key, unaddressed mechanism of immune escape and a novel therapeutic target in glioma. Methods: We analyzed BTLA expression and function within the tumor microenvironment of a Moroccan cohort (n = 44). This was complemented by multiparameter flow cytometry on peripheral blood from glioblastoma (GBM) patients (n = 8) to assess circulating T cell profiles. Findings were corroborated using independent transcriptomic datasets from TCGA and CGGA cohorts. Single-cell RNA-seq and citeSeq identified specific BTLA-expressing cell populations. Results: Elevated BTLA expression was significantly associated with aggressive features and poor overall survival in glioma patients. Mechanistically, BTLA levels were positively correlated with pro-tumorigenic factors, immune infiltration, and immunosuppressive checkpoints. Single-cell and citeSeq analyses revealed that BTLA was primarily expressed by exhausted T cells and conventional type 1 dendritic cells (cDC1) within the GBM microenvironment. Crucially, this phenotype was translated systemically; BTLA defined dysfunctional circulating CD8+ and CD4+ T cells characterized by diminished IFN-\u03b3 production, alongside reduced granzyme B and perforin in CD8+ T cells. Conclusions: Our findings indicate that BTLA may represent a relevant pathway associated with an immunosuppressive glioma microenvironment. The therapeutic potential of targeting this pathway, particularly in combination with PD-1\/PD-L1 blockade, warrants further investigation.<\/jats:p>","DOI":"10.3390\/medsci14040433","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T08:15:56Z","timestamp":1785140156000},"page":"433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Elevated BTLA Expression Correlates with an Immunosuppressive Microenvironment and Defines Dysfunctional Circulating T Cells in Human Glioblastoma"],"prefix":"10.3390","volume":"14","author":[{"given":"Sanaa","family":"Souat","sequence":"first","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadija","family":"El Azhary","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bourdoukh","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdou-samad","family":"Kone","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Qandouci","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zakia","family":"Harmak","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalil","family":"Choukri","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelhakim","family":"Lakhdar","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Hospital Center (UHC) Ibn Rochd, Casablanca 20000, Morocco"},{"name":"Laboratory of Research on Neurologic, Neurosensorial Diseases and Handicap, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-9085","authenticated-orcid":false,"given":"Abdallah","family":"Badou","sequence":"additional","affiliation":[{"name":"Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca 20360, Morocco"},{"name":"City of Innovation and Technology Transfer, Hassan II University of Casablanca, Casablanca 20360, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5045","DOI":"10.1038\/s41598-021-84465-6","article-title":"B2M Overexpression Correlates with Malignancy and Immune Signatures in Human Gliomas","volume":"11","author":"Zhang","year":"2021","journal-title":"Sci. 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