IP-10/CXCL10 expression is induced in tumor stroma in pancreatic cancer and correlates with poor survival in patients

Background and aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) which contributes to radioresistance (Mantoni T et al., Cancer Research 2011), tumor progression and patient prognosis. and to characterize the inflammatory and immune response in pancreatic ductal adenocarcinoma. Methods: We analyzed 50 cytokines, chemokines and growth factors in the supernatant of both mono- and cocultures of PSCs and pancreatic cancer cells (PCCs) in vitro. We then used gene expression analysis in human PDAC samples and also tested the chemotaxis of leukocytes derived from the circulation of PDAC patients ex vivo. Results: IP-10/CXCL10 was the most highly induced chemokine in a coculture system of PSC and PCCs. Its expression was induced in the PSCs by soluble factors from pancreatic cancer cells. Consistent with these observation we found that IP-10 expression was upregulated in human PDAC as compared to matched normal tissue, and IP-10 expression levels were positively correlated with high stroma content. Furthermore, the expression of IP-10 and its receptor CXCR3 in human PDAC were significantly associated with the intratumoral presence of regulatory T cells (Tregs). IP-10 stimulated ex vivo the recruitment of CXCR3⁺ effector T cells as well as CXCR3⁺ Tregs derived from peripheral blood mononuclear cells from patient with PDAC. Furthermore, in an independent cohort of patients, IP-10 correlated with decreased cancer-specific survival. Conclusions: Our findings suggest that, in PDAC patients, CXCR3⁺ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.1 page(s