IL17 producing γδT cells induce angiogenesis and are associated with poor survival in gallbladder cancer patients

• Published in: International journal of cancer 2016-08, Vol.139 (4), p.869-881
• Main Authors: Patil, Rushikesh Sudam, Shah, Sagar Umesh, Shrikhande, Shailesh Vinayak, Goel, Mahesh, Dikshit, Rajesh Prabhakar, Chiplunkar, Shubhada Vivek
• Format: Article
• Language: English
• Subjects: Biomarkers; Cytokines - metabolism; Female; Gallbladder Neoplasms - etiology; Gallbladder Neoplasms - mortality; Gallbladder Neoplasms - pathology; Humans; Interleukin-17 - biosynthesis; Kaplan-Meier Estimate; Lymphocyte Count; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Middle Aged; Neovascularization, Pathologic; Prognosis; Receptors, Antigen, T-Cell, gamma-delta - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Th17; Treg; Tumor Microenvironment; Tγδ17; vascular endothelial growth factor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30134

Despite conventional treatment modalities, gallbladder cancer (GBC) remains a highly lethal malignancy. Prognostic biomarkers and effective adjuvant immunotherapy for GBC are not available. In the recent past, immunotherapeutic approaches targeting tumor associated inflammation have gained importance but the mediators of inflammatory circuit remain unexplored in GBC patients. In the current prospective study, we investigated the role of IL17 producing TCRγδ+ (Tγδ17), CD4+ (Th17), CD8+ (Tc17) and regulatory T cells (Tregs) in pathogenesis of GBC. Analysis by multi‐color flow cytometry revealed that compared to healthy individuals (HI), Tγδ17, Th17 and Tc17 cells were increased in peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TIL) of GBC patients. Tregs were decreased in PBMCs but increased in TILs of GBC patients. The suppressive potential of Tregs from GBC patients and HI were comparable. Serum cytokines profile of GBC patients showed elevated levels of cytokines (IL6, IL23 and IL1β) required for polarization and/or stabilization of IL17 producing cells. We demonstrated that Tγδ17 cells migrate toward tumor bed using CXCL9‐CXCR3 axis. IL17 secreted by Tγδ17 induced productions of vascular endothelial growth factor and other angiogenesis related factors in GBC cells. Tγδ17 cells promote vasculogenesis as studied by chick chorioallantoic membrane assay. Survival analysis showed that Tγδ17, Th17 and Treg cells in peripheral blood were associated with poor survival of GBC patients. Our findings suggest that Tγδ17 is a protumorigenic subtype of γδT cells which induces angiogenesis. Tγδ17 may be considered as a predictive biomarker in GBC thus opening avenues for targeted therapies. What's new? Human T cells expressing γδ‐TCR exhibit potent anti‐tumor activity and are potential candidates for cell‐based therapies. Evidence however also exists of the ability of γδ‐TCR cells to suppress anti‐tumor responses, making deeper insight necessary for the successful clinical application of γδT cell‐based immunotherapies. This study identified IL17‐producing γδT cells (Tγδ17) as a pro‐tumorigenic subtype of γδT cells associated with poor survival in gallbladder cancer (GBC) patients. Tγδ17 cells infiltrate the tumor bed via CXCL9‐CXCR3 axis and IL17 induces pro‐angiogenic factors in GBC cells. Tγδ17 may be considered as a predictive biomarker in GBC, opening up new avenues for targeted therapies.