Prevalence of FOXP3+ Regulatory T Cells Increases During the Progression of Pancreatic Ductal Adenocarcinoma and Its Premalignant Lesions

Abstract

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+ 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.Tumors express many neoantigens originated from the vast number of genetic and epigenetic changes associated with carcinogenesis. Patients with cancer can develop tumor-specific immune responses, although established cancer usually progresses despite the antitumor immune response. It has been suggested that progressive tumors may develop immune escape strategies that include mechanisms to resist immune surveillance and induce immunotolerance. Such mechanisms might include direct deletion of immune effector cells by expression of deathinducing ligands, suppression of tumor-reactive T cells by regulatory T cells (T R ), and tolerization of host T cells by crosspresentation of tumor-derived antigens (1, 2). In contrast to established cancers, there is strong evidence from murine models that specific immune surveillance systems operate at early stages of tumorigenesis, that is, host immune system inhibits the development of tumors (3). It remains to be elucidated how and when effective immune surveillance is overcome during tumor progression. We need effective ...

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

“…Moreover, the population of Foxp3 þ cells in stage IV was significantly larger than those in stage I. However, the prevalence of Foxp3 þ cells is not significantly associated with the overall survival of patients with gastric cancer, in contrast with previous reports on ovarian carcinoma (Wolf et al, 2005) and pancreatic cancer (Hiraoka et al, 2006). The present study is, to our knowledge, the first report describing the prevalence of Foxp3 þ T regs related to the prognosis in gastric cancer.…”

“…Furthermore, the high prevalence of CD4 þ CD25 þ T regs is closely associated with a poor prognosis in ovarian (Curiel et al, 2004) or pancreatic (Liyanage et al, 2002) cancer. Recently, intratumoral Foxp3 þ T regs in ovarian (Wolf et al, 2005) or pancreatic (Hiraoka et al, 2006) cancer were correlated with a poor prognosis (Wolf et al, 2005;Hiraoka et al, 2006). In particular, multivariate analysis in pancreatic cancer (Hiraoka et al, 2006) showed that the prevalence of Foxp3 þ T regs was an independent prognostic factor.…”

“…Recently, intratumoral Foxp3 þ T regs in ovarian (Wolf et al, 2005) or pancreatic (Hiraoka et al, 2006) cancer were correlated with a poor prognosis (Wolf et al, 2005;Hiraoka et al, 2006). In particular, multivariate analysis in pancreatic cancer (Hiraoka et al, 2006) showed that the prevalence of Foxp3 þ T regs was an independent prognostic factor. On the contrary, it has been reported that the clinical outcome was not dependent on the prevalence of Foxp3 þ T regs in TILs in renal cell carcinoma (Siddiqui et al, 2007).…”

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

“…For several solid tumors, there is a clear correlation between high T reg numbers (tumor infiltrating or circulating in the peripheral blood) and a poor prognosis. 10,11,21,22 Although previous reports have indicated an increase of T regs in the peripheral blood of patients with CLL compared with healthy controls, 19,20 their role in disease progression has remained unclear. The objective of the present study was to elucidate the possible clinical relevance of T reg numbers in early stage CLL.…”

“…of T regs (tumor infiltrating or circulating in the peripheral blood) and a poor prognosis, [10][11][12] we investigated the role of T regs in early stage CLL.…”