Clinical Significance of Folate Receptor β-expressing Tumor-associated Macrophages in Pancreatic Cancer

To examine the appearance and distribution of folate receptor beta-expressing (FR beta(+)) macrophages in the pancreatic tumor microenvironment and their relationship to metastasis and prognosis in pancreatic cancer patients. Tumor samples were obtained from 76 patients with pancreatic cancer who underwent curative resection. None of these patients had received any preoperative chemotherapy or radiotherapy. Both FR beta(+) and tumor-infiltrating (CD68(+)) macrophages were examined in each tumor specimen by immunohistochemical and immunofluorescence staining using a newly developed anti-human FR beta monoclonal antibody and CD68 antibody. The appearance, distribution, expression of vascular endothelial growth factor (VEGF) on FR beta-expressing or CD68(+) macrophages, and tumor microvessel density (MVD) were assessed. Log rank test and Cox proportional hazard regression were used to investigate the associations among CD68(+) or FR beta(+) macrophages, clinicopathologic factors, and overall survival. FR beta(+) macrophages were prominent in the perivascular regions of the tumor-invasive front and a specific subset with VEGF expression in the CD68(+) macrophages. A high number of FR beta(+) macrophages showed a positive association with high MVD, a high incidence of hematogenous metastasis, and a poor prognosis in pancreatic cancer patients. FR beta(+) macrophages are a novel subset of tumor-associated macrophages in pancreatic cancer and may play an important role in the tumor microenvironment in association with systemic metastasis through the interaction with tumor cells and vessels. FR beta(+) macrophages may be promising a targeting therapy for pancreatic cancer.