Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinorna and its premalignant lesions

Purpose: Antitumor immune response changes drastically during the progression of cancers. Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4(+)CD25(+) regulatory T cells (T-R) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of T-R in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma. Experimental Design: We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3(+)CD4(+)CD25(+) T-R in the CD4(+) T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions. Results: The prevalence of T-R was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P < 0.0001). The increased prevalence of T-R was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of T-R, and this was independent of other survival factors (P < 0.0001). Infiltration of intraepithelial CD8(+)TIA-1(+) cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of T-R increased significantly during the progression of premalignant lesions. Conclusions: T-R play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of T-R seems to be a marker of poor prognosis.