Distribuzione delle cellule CD4+CD25+FoxP3+(Treg) nel sangue periferico ed interazioni dinamiche della reazione immunitaria nei pazienti con adenocarcinoma del pancreas

OBJECTIVES: CD4+CD25+FOXP3+ T cells are an heterogeneous population of cells playing a key role in maintenance of the immune system’s tolerance of both foreign and self-antigens. They can inibit immune responses mediated by T effector cells. Patients with a variety of cancers have an enlarged pool of Treg in their peripheral blood, in tumor-draining lymph nodes and in the tumor microenvironment. Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatement having little impact on disease course. Poorly prognosis in pancreatic cancer (PC) patients has been correlated with increase of Treg in peripheral blood, lymph nodes et tumor tissue. Despite the advanced understanding of the mechanism of cancer evasion, the exact mechanism and clinical significance of Treg elevation in PC patients remains unclear. Further work is required to investigate of wich of Treg specific subpopulation is involved in pancreatic cancer developement to provide greater insights into potential mechanisms of cancer evasion and to develope an array of treatements that will inhibit spacific pathways that mediate evolution and progression of ACP. To evaluate the distibution of Tregs in peripheral blood of PC patients, in the present prospectic study the percentage of circulating rTregs and aTreg has been compared to that of healthy volunteers, colon cancer patients and inflammatory diseases patients. Furthemore, we analyse the balance of the different subsets of Tregs in peripheral blood in PC patients and the correlation between the prevalence of circulating Tregs in PC patients and their clinico-pathological findings and outcomes. METHODS: Among a total of 29 patients with ductal adenocarcinoma of the pancreas, 24 underwent pancreatectomy and 5 biliopancreatic diversion. Their peripheral blood mononuclear cells (PBMCs) were analysed to determine the proportion of CD4+CD25+Foxp3+ T cells (Tregs), as a percentage of the total CD4+ cells, by FACScan analysis after labeling with anti-CD4, anti-CD25, anti-CD45 and anti-Foxp3 antibodies. Clinical stages were classified according to the TNM classification. RESULTS: The percentage of CD4+CD25+++CD45RA- Foxp3hi (aTreg) cells among the PBMCs was significatively increased in PC patients compared with healty donors (HD) (P<0,001), colon cancer patients and patients with inflammatory diseases (P<0,001). The analys of rTreg/aTreg balance showed an evolutive inflammatory profil in PC patients compared to that of healthy donors and confirm the Treg cell differentiation dynamics and interactions. A positive correlation was found between the percentage of CD4+CD25++CD45RA+FoxP3low (nTreg), CD4+CD25+++CD45-RAFoxp3hi (aTreg) and the patients age. No correlation was found between the percentage of circulating Treg and clinical stages and survival. CONCLUSIONS: The increase in CD4+CD25+++CD45RA-FoxP3hi Treg cells may be related to immunosuppression and tumor progression in patients with ductal pancreatic cancer. Their removal can boost the antitumor immunity with the potential to achieve therapeutic impacts. Further studies are required: - To determine the mechanisms exact of tumor evasion and of Treg cells elevation in peripheral blood, draining lymph nodes and tumor tissue in cancer patients. - to evaluated dynamic interactions between different subsets of Treg cells and their clinical significance. The immunological monitoring of Treg may be useful to predict the prognosis for patients with pancreatic cancer. Additionally, an increase in our understanding of exact mechanism of Treg-mediated suppression will offer insights into potential alternatives for inhibiting, in a selective way, specific Treg activity and enhance immunotherapeutic potentials.