IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival.

Serena Lunardi,Owen J Sansom,Michael A Silva,Manuela Carvalho-Gaspar,Thomas B Brunner,Ross C Carter,Osama Al-Assar,Klaus-Peter Janssen,Colin J Mckay,Sabira Yameen,Stefano D’Ugo,Nigel B Jamieson,Kristin L Griffiths,Ruth J Muschel,Gabriele Spoletini,Su Yin Lim

doi:10.18632/oncotarget.2519

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the 10th most common cancer worldwide and ranks fourth in cancer-related mortality in the USA and fifth in the UK [1, 2]
We found that interferon-γ inducible protein 10 (IP-10) and CXCR3 levels correlated with the expression of CD3ε, CD4, FOXP3, CTLA4, CD39 and IDO1, molecules characteristically expressed by regulatory T cells (Tregs) (Figure 5D)
Together with other factors already known to be secreted by pancreatic stellate cells (PSCs) such as IL-8, IL-6 and stromal cell-derived factor-1α (SDF-1α), we found that human PSCs secrete leukemia inhibitory factor (LIF), IL-1Rα, IL-15, GROα, eotaxin and IP-10

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the 10th most common cancer worldwide and ranks fourth in cancer-related mortality in the USA and fifth in the UK [1, 2]. PSCs lose their vitamin A storage droplets, express vimentin and α-smooth muscle actin and release high levels of extracellular matrix (ECM) proteins and growth factors that promote proliferation, survival and migration of PCCs [3]. This desmoplastic reaction acts as a physical obstacle to drug delivery and impairs the response to radiotherapy [4, 5]. It was reported that high levels of Galectin-1, secreted by the PSCs, induced apoptosis of CD4+ and CD8+ T cells [7]. The mechanisms by which PSCs influence the immunoresponse are not completely understood and remain subject of active research [10, 11]

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Results

Conclusion