title: IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival.
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.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Lunardi
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom.
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Su Yin
authors.initials: SY
authors.lastname: Lim
authors.affiliation: Jenner Institute, University of Oxford, Old Road Campus, OX2 7BN, Oxford, United Kingdom.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Griffiths
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Manuela
authors.initials: M
authors.lastname: Carvalho-Gaspar
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Osama
authors.initials: O
authors.lastname: Al-Assar
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Sabira
authors.initials: S
authors.lastname: Yameen
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Carter
authors.affiliation: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: McKay
authors.affiliation: Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Spoletini
authors.affiliation: Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: D'Ugo
authors.affiliation: Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silva
authors.affiliation: Beatson Institute of Cancer Research, Garscube Estate, Glasgow, G61 1BD, United Kingdom.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Department of Surgery, Technische Universitaet Muenchen, 81675 Muenchen, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom. Department of Radiation Oncology, University Hospitals Freiburg, 79106 Freiburg, Germany.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Brunner
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D058954:Pancreatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10