Il17 Producing Gamma Delta T Cells Induce Angiogenesis And Are Associated With Poor Survival In Gallbladder Cancer Patients

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 TCR gamma delta(+) (T gamma delta 17), 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), T gamma delta 17, 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 IL1 beta) required for polarization and/or stabilization of IL17 producing cells. We demonstrated that T gamma delta 17 cells migrate toward tumor bed using CXCL9-CXCR3 axis. IL17 secreted by T gamma delta 17 induced productions of vascular endothelial growth factor and other angiogenesis related factors in GBC cells. T gamma delta 17 cells promote vasculogenesis as studied by chick chorioallantoic membrane assay. Survival analysis showed that T gamma delta 17, Th17 and Treg cells in peripheral blood were associated with poor survival of GBC patients. Our findings suggest that T gamma delta 17 is a protumorigenic subtype of gamma delta T cells which induces angiogenesis. T gamma delta 17 may be considered as a predictive biomarker in GBC thus opening avenues for targeted therapies.