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

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.

[1]  Umar Mahmood,et al.  Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. , 2015, Cancer cell.

[2]  J. Gribben,et al.  Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. , 2013, Gastroenterology.

[3]  W. Frankel,et al.  Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. , 2013, Cancer research.

[4]  F. Alvarez,et al.  Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance , 2013, Hepatology.

[5]  A. Jemal,et al.  Cancer statistics, 2013 , 2013, CA: a cancer journal for clinicians.

[6]  I. Andrulis,et al.  Tumoral Lymphocytic Infiltration and Expression of the Chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry , 2012, Clinical Cancer Research.

[7]  K. Odunsi,et al.  CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. , 2012, Cancer research.

[8]  H. Zeh,et al.  NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. , 2012, Cancer research.

[9]  G. Montrucchio,et al.  Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome. , 2012, Experimental and therapeutic medicine.

[10]  Y. Miao,et al.  High expression of Galectin‐1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer , 2012, International journal of cancer.

[11]  Carlos Cuevas,et al.  Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[12]  J. Norman,et al.  Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression , 2012, Developmental cell.

[13]  R. Dhir,et al.  Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion , 2012, Molecular Cancer.

[14]  A. Masamune,et al.  Pancreatic stellate cells radioprotect pancreatic cancer cells through β1-integrin signaling. , 2011, Cancer research.

[15]  A. Luster,et al.  CXCR3 ligands: redundant, collaborative and antagonistic functions , 2011, Immunology and cell biology.

[16]  A. Katritzky,et al.  Chemokine receptor CXCR3 promotes growth of glioma. , 2011, Carcinogenesis.

[17]  A. Casrouge,et al.  Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. , 2011, The Journal of clinical investigation.

[18]  D. Kranz.  Faculty Opinions recommendation of Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. , 2010 .

[19]  James O. Jones,et al.  Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α , 2010, Science.

[20]  Yan Zhao,et al.  Pancreatic Stellate Cells Increase the Invasion of Human Pancreatic Cancer Cells through the Stromal Cell-Derived Factor-1/CXCR4 Axis , 2010, Pancreatology.

[21]  J. Shapiro,et al.  CXCR3/ligands are significantly involved in the tumorigenesis of basal cell carcinomas. , 2010, The American journal of pathology.

[22]  J. Ferlay,et al.  Estimates of cancer incidence and mortality in Europe in 2008. , 2010, European journal of cancer.

[23]  L. Bradley.  Faculty Opinions recommendation of The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. , 2009 .

[24]  P. Gimotty,et al.  CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model , 2009, Molecular Cancer Therapeutics.

[25]  A. Keegan.  Faculty Opinions recommendation of Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. , 2009 .

[26]  M. Jenkins,et al.  Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin. , 2009, Immunity.

[27]  Chen Dong,et al.  CCR6 Regulates the Migration of Inflammatory and Regulatory T Cells1 , 2008, The Journal of Immunology.

[28]  A. Masamune,et al.  Fibrinogen induces cytokine and collagen production in pancreatic stellate cells , 2008, Gut.

[29]  S. Kelsen,et al.  Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[30]  David Goldstein,et al.  Pancreatic stellate cells: partners in crime with pancreatic cancer cells. , 2008, Cancer research.

[31]  S. Arora,et al.  Expression of Interferon-Gamma- Inducible Protein-10 and Its Receptor CXCR3 in Chronic Pancreatitis , 2007, Pancreatology.

[32]  D. Tuveson,et al.  Dynamics of the immune reaction to pancreatic cancer from inception to invasion. , 2007, Cancer research.

[33]  J. Lillard,et al.  CXCR3 axis: role in inflammatory bowel disease and its therapeutic implication. , 2007, Endocrine, metabolic & immune disorders drug targets.

[34]  B. Shalmon,et al.  CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. , 2007, Cancer research.

[35]  J. Ferlay,et al.  Estimates of the cancer incidence and mortality in Europe in 2006. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[36]  M. Grimm,et al.  Ras-induced modulation of CXCL10 and its receptor splice variant CXCR3-B in MDA-MB-435 and MCF-7 cells: relevance for the development of human breast cancer. , 2006, Cancer research.

[37]  S. Hirohashi,et al.  Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions , 2006, Clinical Cancer Research.

[38]  Michael G. Johnson,et al.  Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. , 2006, Cancer research.

[39]  S. Kelsen,et al.  CXCR3 surface expression in human airway epithelial cells: cell cycle dependence and effect on cell proliferation. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[40]  T. Bieber,et al.  Type I interferon-associated recruitment of cytotoxic lymphocytes: a common mechanism in regressive melanocytic lesions. , 2005, American journal of clinical pathology.

[41]  T. Manabe,et al.  Pivotal Role of CXCR3 in Melanoma Cell Metastasis to Lymph Nodes , 2004, Cancer Research.

[42]  D. Munn,et al.  Ligation of B7-1/B7-2 by Human CD4+ T Cells Triggers Indoleamine 2,3-Dioxygenase Activity in Dendritic Cells1 , 2004, The Journal of Immunology.

[43]  Sergio Romagnani,et al.  An Alternatively Spliced Variant of CXCR3 Mediates the Inhibition of Endothelial Cell Growth Induced by IP-10, Mig, and I-TAC, and Acts as Functional Receptor for Platelet Factor 4 , 2003, The Journal of experimental medicine.

[44]  T. Eberlein,et al.  Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma1 , 2002, The Journal of Immunology.

[45]  N. Giese,et al.  Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice , 2002, Cancer Gene Therapy.

[46]  R. Dorsey,et al.  Expression of the Chemokines IP-10 and Mig in IL-10 Transduced Tumors , 2001, Journal of immunotherapy : official journal of the Society for Biological Therapy.

[47]  E. Hudson,et al.  Differential expression and responsiveness of chemokine receptors (CXCR1–3) by human microvascular endothelial cells and umbilical vein endothelial cells , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  Pau Serra,et al.  Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice , 2006, Nature Immunology.

[49]  Melinda Fitzgerald,et al.  Immunol. Cell Biol. , 1995 .

[50]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.