title: Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer.
abstract: The host immune system plays a significant role in tumor control, although most cancers escape immune surveillance through a variety of mechanisms. The aim of the present study was to evaluate the clinicopathological significance of a novel co-inhibitory receptor, B and T lymphocyte attenuator (BTLA), the anergy cell marker Casitas-B-lineage lymphoma protein-b (Cbl-b), and clinical implications of tumor-infiltrating immune cells in gallbladder cancer (GBC) tissues. We investigated 211 cases of GBC, 21 cases of chronic cholecystitis (CC), and 11 cases of xanthogranulomatous cholecystitis (XGC) using immunohistochemistry to detect tissue-infiltrating immune cells and their expression of BTLA and Cbl-b, and carried out correlation and survival analyses. The density of infiltrating T cells was significantly higher in CC and XGC than in GBC. The density ratio of BTLA(+) cells to CD8(+) T cells (BTLA/CD8) and that of Cbl-b(+) cells to CD8(+) T cells (Cbl-b/CD8) were significantly higher in GBC than in CC and XGC. The FOXP3/CD4, BTLA/CD8, and Cbl-b/CD8 ratios were significantly correlated with each other, and also with malignant phenotypes. Survival analyses revealed that a lower density of tumor-infiltrating CD8(+) cells, and higher Foxp3/CD4, BTLA/CD8, and Cbl-b/CD8 ratios were significantly associated with shorter overall survival and disease-free survival in GBC patients. Multivariate analyses showed that M factor, perineural invasion, BTLA/CD8, and Cbl-b/CD8 were closely associated with shorter overall survival. These findings suggest that higher ratios of BTLA/CD8 and Cbl-b/CD8 are independent indicators of unfavorable outcome in GBC patients, and that upregulation of BTLA in cancer tissues is involved in inhibition of antitumor immunity.
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.|Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.|Division of Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.|Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Oguro
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ino
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.|Research Division of Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.|Research Division of Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuno
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Esaki
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nara
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kishi
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.|Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Kosuge
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.|Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hiraoka
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D000368:Aged; D005260:Female; D005706:Gallbladder Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*
chemical_list: C482586:BTLA protein, human; D011971:Receptors, Immunologic; D050721:Proto-Oncogene Proteins c-cbl
keywords: Anergy; BTLA; gallbladder cancer; immune checkpoint; immune microenvironment