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The aim of the present study was to evaluate the clinicopathological significance of a novel co\u2010inhibitory receptor, B and T lymphocyte attenuator (BTLA<\/jats:styled-content>), the anergy cell marker Casitas\u2013B\u2010lineage lymphoma protein\u2010b (Cbl\u2010b), and clinical implications of tumor\u2010infiltrating immune cells in gallbladder cancer (GBC<\/jats:styled-content>) tissues. We investigated 211 cases of GBC<\/jats:styled-content>, 21 cases of chronic cholecystitis (CC<\/jats:styled-content>), and 11 cases of xanthogranulomatous cholecystitis (XGC<\/jats:styled-content>) using immunohistochemistry to detect tissue\u2010infiltrating immune cells and their expression of BTLA<\/jats:styled-content> and Cbl\u2010b, and carried out correlation and survival analyses. The density of infiltrating T cells was significantly higher in CC<\/jats:styled-content> and XGC<\/jats:styled-content> than in GBC<\/jats:styled-content>. The density ratio of BTLA<\/jats:styled-content>+<\/jats:sup> cells to CD<\/jats:styled-content>8+<\/jats:sup> T cells (BTLA<\/jats:styled-content>\/CD<\/jats:styled-content>8) and that of Cbl\u2010b+<\/jats:sup> cells to CD<\/jats:styled-content>8+<\/jats:sup>T cells (Cbl\u2010b\/CD<\/jats:styled-content>8) were significantly higher in GBC<\/jats:styled-content> than in CC<\/jats:styled-content> and XGC<\/jats:styled-content>. The FOXP<\/jats:styled-content>3\/CD<\/jats:styled-content>4, BTLA<\/jats:styled-content>\/CD<\/jats:styled-content>8, and Cbl\u2010b\/CD<\/jats:styled-content>8 ratios were significantly correlated with each other, and also with malignant phenotypes. Survival analyses revealed that a lower density of tumor\u2010infiltrating CD<\/jats:styled-content>8+<\/jats:sup> cells, and higher Foxp3\/CD<\/jats:styled-content>4, BTLA<\/jats:styled-content>\/CD<\/jats:styled-content>8, and Cbl\u2010b\/CD<\/jats:styled-content>8 ratios were significantly associated with shorter overall survival and disease\u2010free survival in GBC<\/jats:styled-content> patients. Multivariate analyses showed that M factor, perineural invasion, BTLA<\/jats:styled-content>\/CD<\/jats:styled-content>8, and Cbl\u2010b\/CD<\/jats:styled-content>8 were closely associated with shorter overall survival. These findings suggest that higher ratios of BTLA<\/jats:styled-content>\/CD<\/jats:styled-content>8 and Cbl\u2010b\/CD<\/jats:styled-content>8 are independent indicators of unfavorable outcome in GBC<\/jats:styled-content> patients, and that upregulation of BTLA<\/jats:styled-content> in cancer tissues is involved in inhibition of antitumor immunity.<\/jats:p>","DOI":"10.1111\/cas.12825","type":"journal-article","created":{"date-parts":[[2015,9,23]],"date-time":"2015-09-23T12:30:53Z","timestamp":1443011453000},"page":"1750-1760","source":"Crossref","is-referenced-by-count":59,"title":["Clinical significance of tumor\u2010infiltrating immune cells focusing on BTLA<\/scp> and Cbl\u2010b in patients with gallbladder cancer"],"prefix":"10.1111","volume":"106","author":[{"given":"Seiji","family":"Oguro","sequence":"first","affiliation":[{"name":"Division of Molecular Pathology National Cancer Center Research Institute Tokyo Japan"},{"name":"Division of Pathology and Clinical Laboratories 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