Gamma-delta T cells stimulate IL-6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma

Adrian M Seifert,Jürgen Weitz,Daniela E Aust,Julian List,Rahel Decker,Max Heiduk,Ann-Christin Meinecke,Janusz Von Renesse,Lena Seifert,Thilo Welsch

doi:10.1007/s00432-020-03367-8

Abstract

IntroductionThe immunosuppressive tumor microenvironment promotes progression of pancreatic ductal adenocarcinoma (PDAC). γδ T cells infiltrate the pancreatic tumor stroma and support tumorigenesis through αβ T cell inhibition. Pancreatic stellate cell (PSC) activation contributes to pancreatic fibrosis in PDAC, limiting the delivery and efficacy of therapeutic agents. Whether γδ T cells have direct effects on PSC activation is unknown.MethodsIn this study, we analyzed tumor tissue from 68 patients with PDAC and determined the frequency and location of γδ T cells using immunohistochemistry and immunofluorescence. PDAC samples from the TCGA database with low and high TRGC2 expression were correlated with the expression of extracellular matrix genes. Further, PSCs were isolated from pancreatic tumor tissue and co-cultured with γδ T cells for 48 hours and cytokine production was measured using a cytometric bead array.Resultsγδ T cells infiltrated the pancreatic tumor stroma and were located in proximity to PSCs. A high infiltration of γδ T cells was associated with increased expression of several extracellular matrix genes in human PDAC. In vitro, γδ T cells stimulated IL-6 production by PDAC-derived PSCs.Conclusionγδ T cells activated PSCs and modulation of this interaction may enhance the efficacy of combinational therapies in human PDAC.

Highlights

The immunosuppressive tumor microenvironment promotes progression of pancreatic ductal adenocarcinoma (PDAC). γδ T cells infiltrate the pancreatic tumor stroma and support tumorigenesis through αβ T cell inhibition
Our results suggest that γδ T cells may have a direct effect on Pancreatic stellate cell (PSC) and that γδ T-cell modulation in PDAC may relieve local immunosuppression leading to increased invasion of cytotoxic T cells
Γδ T cells are located in proximity to PSCs in the pancreatic tumor stroma Using immunofluorescence staining for the γδ T-cell receptor and alpha-smooth muscle actin, a differentiation marker for activated PSCs, we found that γδ T cells were located near PSCs in the pancreatic tumor stroma (Fig. 3a)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and projected to become the second leading cause of cancer-related deaths by 2030 (Yadav and Lowenfels 2013). Journal of Cancer Research and Clinical Oncology (2020) 146:3233–3240 of extracellular matrix (ECM) proteins and secretion of cytokines, such as transforming growth factor β (TGFβ) and interleukin-6 (IL-6) (Wu et al 2017; Hwang et al 2008). These factors promote fibrosis, tumor cell proliferation, angiogenesis, immunosuppression, and therapeutic resistance, leading to disease progression (Vonlaufen et al 2008). Antigen-presenting cells, including M2-polarized tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), support PDAC progression by inducing adaptive immune suppression (Pylayeva-Gupta et al 2012; Bayne et al 2012; Zhu et al 2014). Our results suggest that γδ T cells may have a direct effect on PSCs and that γδ T-cell modulation in PDAC may relieve local immunosuppression leading to increased invasion of cytotoxic T cells

Materials and methods

Discussion

Compliance with ethical standards