PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer.

Adrian M Seifert,Rahel Decker,Janusz Von Renesse,Antje Tunger,Rebekka Wehner,Daniela E Aust,Jürgen Weitz,Lena Seifert,Marc Schmitz,Thilo Welsch,Christoph Reissfelder,Annabel Eymer,Max Heiduk

doi:10.3390/cancers12102756

Abstract

Simple SummaryPancreatic cancer is a devastating disease and among the most immune-resistant tumor types. Single-agent immunotherapy has not demonstrated clinical benefits in pancreatic cancer patients, and combinational therapies targeting multiple mechanisms of immunosuppression are likely needed. T cell activation in lymph nodes is required for the efficacy of immunotherapy. Here, we phenotypically and functionally analyze T cells from tumor-draining lymph nodes, blood and tumors from patients with pancreatic cancer to decipher unknown immunosuppressive mechanisms and to identify potential immunotherapeutic targets.Pancreatic ductal adenocarcinoma (PDAC) is characterized by a mostly immunosuppressive microenvironment. Tumor-draining lymph nodes (TDLN) are a major site for priming of tumor-reactive T cells and also tumor metastasis. However, the phenotype and function of T cells in TDLNs from PDAC patients is unknown. In this study, lymph nodes from the pancreatic head (PH), the hepatoduodenal ligament (HDL) and the interaortocaval (IAC) region were obtained from 25 patients with adenocarcinoma of the pancreatic head. Additionally, tumors and matched blood were analyzed from 16 PDAC patients. Using multicolor flow cytometry, we performed a comprehensive analysis of T cells. CD4+ T cells were the predominant T cell subset in PDAC-draining lymph nodes. Overall, lymph node CD4+ and CD8+ T cells had a similar degree of activation, as measured by CD69, inducible T cell co-stimulator (ICOS) and CD137 (4-1BB) expression and interferon-γ (IFNγ) secretion. Expression of the inhibitory receptor programmed death 1 (PD-1) by lymph node and tumor-infiltrating regulatory T cells (Tregs) correlated with lymph node metastasis. Collectively, Treg cells and PD-1 are two relevant components of the immunosuppressive network in PDAC-draining lymph nodes and may be particularly attractive targets for combinatorial immunotherapeutic strategies in selected patients with node-positive PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with fewer than 9% of patients surviving five years [1]
The percentages of CD3+ T cells among leukocytes was similar between lymph node regions (Figure 1B)
The CD4+ Tcells associated node-positive cells (Tconv) to Treg as well as the CD8+ T cell to Treg ratio was similar between lymph node locations (Figure 1D,E)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with fewer than 9% of patients surviving five years [1]. Lymph node (LN) metastases occur in approximately two-thirds of patients with resectable PDAC and are associated with poor prognosis [2,3]. The use of a single-agent immune checkpoint blockade has not demonstrated clinical benefits, a very limited number of PDAC patients has been enrolled in these studies [4,5,6]. T cell activation in regional lymph nodes is required for the efficacy of inhibitory receptor blockade [7]. There is relevant data suggesting a heterogeneity with regard to the immunogenicity of PDAC [8]

Methods

Results

Conclusion