Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer.
Clinical significance of tumor-infiltrating immune cells focusing on BTLA and Cbl-b in patients with gallbladder cancer.
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DOI：
10.1111/cas.12825
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发表时间：
2015-12
期刊：
影响因子：
5.7
通讯作者：
Hiraoka N
中科院分区：
文献类型：
--
作者：
Oguro S;Ino Y;Shimada K;Hatanaka Y;Matsuno Y;Esaki M;Nara S;Kishi Y;Kosuge T;Hiraoka N
宿主免疫系统在肿瘤控制中起着重要作用，尽管大多数癌症通过各种机制逃避免疫监视。本研究的目的是评价一种新型共抑制受体，B和T淋巴细胞衰减因子（BTLA），无反应性细胞标志物Casitas-B谱系淋巴瘤蛋白-B（Cbl-B）的临床病理学意义，以及胆囊癌（GBC）组织中肿瘤浸润免疫细胞的临床意义。采用免疫组织化学方法检测211例GBC、21例慢性胆囊炎（CC）和11例黄色肉芽肿性胆囊炎（XGC）组织浸润免疫细胞及其BTLA和Cbl B的表达，并进行相关性分析和生存分析。CC和XGC中浸润的T细胞密度显著高于GBC。GBC中BTLA +/CD 8 + T细胞密度比（BTLA/CD 8）和Cbl-B+/CD 8 +T细胞密度比（Cbl-B/CD 8）均显著高于CC和XGC。FOXP 3/CD 4、BTLA/CD 8和Cbl-B/CD 8比值彼此显著相关，并且与恶性表型也显著相关。生存分析显示，较低密度的肿瘤浸润性CD 8+细胞和较高的Foxp 3/CD 4、BTLA/CD 8和Cbl-B/CD 8比值与GBC患者较短的总生存期和无病生存期显著相关。多变量分析显示，M因子、神经周围浸润、BTLA/CD 8和Cbl-B/CD 8与总生存期缩短密切相关。这些发现表明，较高的BTLA/CD 8和Cbl-B/CD 8比率是GBC患者不良结局的独立指标，并且癌组织中BTLA的上调涉及抗肿瘤免疫的抑制。
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.