title: Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis.
abstract: Background:Infiltration of immune cells and immune microenvironment determine the proliferative activity of the tumor and metastasis. The aim of this study was to analyze the influence of activation or suppression of the immune response mediators on the prognosis of biliary tract cancer (BTC).Methods:We searched Pubmed, Web of Science, Embase and The Cochrane Library for relevant literatures until June 2016. The quality of studies was assessed by QUADAS-2 and NOS tools. Forest and funnel plots and all statistical analyses were generated by using Review Manager 5.3. The bias of included studies was estimated by Egger's test using Meta R package.Results:A total of 2339 patients from 12 studies were finally enrolled in this meta-analysis. Patients with high expression of immune active factors, intraepithelial tumor-infiltrating CD4+ , CD8+, and Foxp3+ T lymphocytes, MHC I, NKG2D, showed a better overall survival (OS) than those with low expression (HR=0.52, 95% CI=0.41-0.67, P<0.00001). On the contrary, the high expression of immune suppressive factors (CD66b+ neutrophils, Neutrophil-lymphocyte ratio, Intratumoral IL-17+ cells and PD-1+/CD8+ TILs) was significantly associated with poor OS (HR=1.79, 95% CI=1.44-2.22, P<0.00001). A further analysis of therapies targeting tumor microenvironment modulation showed that the median progression free survival (PFS) for BTC patients who received adjuvant immunotherapy was longer than those who received surgery or chemotherapy alone, and the estimated pooled mean difference demonstrated a highly significant improvement (MD =2.33; 95% CI: 0.63-4.02, P=0.007). The total effect of PFS and OS was statistically longer in experimental group, compared to patients in control groups, respectively (PFS: RR=1.25; 95% CI: 1.08-1.46, P=0.004; OS: RR=1.16; 95% CI: 1.07-1.27, P=0.0006). In subgroup meta-analysis of studies on 6-, 12- and 18-month PFS and OS, it showed that adjuvant immunotherapy could improve the 6-month PFS (RR=1.23; 95% CI: 1.05-1.44, P=0.009), and 6-month OS (RR=1.17; 95% CI: 1.06-1.30, P=0.002).Conclusions:So given the above issue, our meta-analysis confirmed that the level of immune mediators could be a predicative factor for prognosis of BTC patients, and immunotherapy regimens by modulating the tumor microenvironment was superior for enhancing median PFS, 6-month PFS and OS.
authors.affiliation: Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Tumor Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.affiliation: Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Jinghan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Xijing
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Fuping
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Linfang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.; Shanghai Cell Therapy Research Institute, Shanghai, China.
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.affiliation: Laboratory of Gene and Viral Therapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.; Department of Biotherapy, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University of Chinese PLA, Shanghai, China.; Shanghai Cell Therapy Research Institute, Shanghai, China.; Ningbo No.5 Hospital (Ningbo Cancer Hospital), Ningbo, China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
keywords: biliary tract cancer; immune response mediators; immunotherapy; meta-analysis.