Authors:
Agnes Witkiewicz, Jonathan R. Brody, Brandice Durkan, T Timothy Williams, and Charles J. Yeo
Summary:
Objective: This study was designed to evaluate a novel mechanism by which metastatic pancreatic ductal adenocarcinoma (PDA) cells evade destruction by the immune system.
Background: A crucial feature of metastatic PDA cells is their ability to avoid immune surveillance. The mechanism by which PDA cells escape immune detection and survive in lymph nodes is poorly understood. One possible mechanism by which PDA cells may escape immune destruction is through up-regulation of indoleamine 2,3-dioxygenase (IDO), an enzyme that can starve T lymphocytes of tryptophan and cause cytotoxic T cells to arrest and become non-reactive.
Methods: Seventeen cases of PDA were evaluated by immunohistochemistry
for expression of IDO in tumor cells and the number of FOXP3 expressing regulatory T cells. To validate the expression of IDO, western blot analysis for IDO was performed on pancreatic cancer cell line protein lysates.
Results: Up-regulation of IDO in metastatic PDA cells increases the number of regulatory T cells which inhibit lymphocytic proliferation. Cytoplasmic IDO expression was present in all tumors with lymph node metastasis. Corresponding metastatic foci showed stronger IDO expression when compared to the primary tumor. Three non-metastatic PDA were negative or only focally positive for IDO. FOXP3 regulatory T cells were increased in the lymph nodes containing metastatic tumor cells expressing IDO. IDO expression in PDA was independent of tumor histologic grade. IDO expression was confirmed via western blot analysis on several pancreatic cancer cell lines.
Conclusions: These data provide the first evidence for the hypothesis that metastatic PDA cells select for over expression of IDO to evade immunologic detection. Future studies will define whether IDO expression in the PDA lymph node metastasis correlates with a decreased survival. Further, manipulation of IDO expression in PDA may be useful to enhance immunotherapeutic strategies against PDA.
Source:
Abstract (American College of Surgeons, Southern Surgical Association 119th Annual Session, December 3-5, 2007, conference paper abstracts, page 18)