Oncotarget

Clinical Research Papers:

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

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

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Oncotarget. 2014; 5:11064-11080. https://doi.org/10.18632/oncotarget.2519

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Abstract

Serena Lunardi1, Nigel B. Jamieson2, Su Yin Lim1, Kristin L. Griffiths3, Manuela Carvalho-Gaspar1, Osama Al-Assar1, Sabira Yameen1, Ross C. Carter2, Colin J. McKay2, Gabriele Spoletini4, Stefano D’Ugo4, Michael A. Silva4, Owen J. Sansom5, Klaus-Peter Janssen6, Ruth J. Muschel1,*, Thomas B. Brunner1,7,*

1Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom

2West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom

3Jenner Institute, University of Oxford, Old Road Campus, OX2 7BN, Oxford, United Kingdom

4Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Oxford, United Kingdom

5Beatson Institute of Cancer Research, Garscube Estate, Glasgow, G61 1BD, United Kingdom

6Department of Surgery, Technische Universitaet Muenchen, 81675 Muenchen, Germany

7Department of Radiation Oncology, University Hospitals Freiburg, 79106 Freiburg, Germany

*These authors have contributed equally to this work

Correspondence to:

Serena Lunardi, e-mail: serena.lunardi@oncology.oxon.org

Keywords: pancreatic cancer, pancreatic stellate cells, tumor stroma, IP-10, CXCL10

Received: May 04, 2014     Accepted: September 24, 2014     Published: November 11, 2014

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.


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