IgG4 Reaction in Biliary Cancers – Signification and Mechanism
Kenichi Harada, Yasuni Nakanuma. Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan
Background: IgG4-related diseases are characterized by the increased serum IgG4 and the infiltration of marked IgG4+ plasma cells, but malignant tumors mimicking IgG4-related diseases have been reported. IL-10 is an important regulatory cytokine associated with the differentiation of IgG4-producing plasma cells. In this study, the signification and mechanism of IgG4 reaction were investigated in extrahepatic biliary cancers.
Design: Immunohistochemistry of IgG4, CD8, HLA-DR, CD80, CD86, and Foxp3 was performed using 68 cases of surgical specimens from patients with 39 gallbladder cancers, 21 common bile duct cancers, and 8 cancers of the papilla of Vater. Moreover, using two cultured cell lines originated from human cholangiocarcinoma, molecular analysis for Foxp3 and IL-10 was performed.
Results: 1. Association between IgG4 reaction and immune surveillnce. Immunohistochemistry for IgG4 and CD8 was performed using 68 cases of biliary cancers including common bile duct cancers, gallbladder cancers, and cancers of the papilla of Vater. Although IgG4+ cells were few or none in the majority of cases, ≥10 and ≥50 cells/high power field [HPF] were found in 37% and 6% of cases, respectively. In the cases with over 10 IgG4+ cells/HPF, cytotoxic CD8+ T cells were few within tumor, suggesting the evasion of immune surveillance. 2. Biliary cancers as non-professional antigen presenting cells (APCs). Immunohistochemistry revealed that MHC class II molecule (HLA-DR)-positive and costimulatory molecules (CD80 and CD86)-negative tumors indicating the possible induction of IL-10-producing regulatory T cells (anergy T cells) were found in 42%, and the number of IgG4+ cells in these cases was higher than those of the others. 3. Biliary cancers as Foxp3+ regulatory cells. The antibody recognizing N terminus of Foxp3 highlighted cancer cells as well as Treg cells and Foxp3+ cancers had more numerous IgG4+ cells than Foxp3− ones. In vitro study using cultured human cholangiocarcinoma cell lines demonstrated the presence of splicing variant of Foxp3 mRNA and the expression of IL-10 mRNA, suggesting the regulatory function of Foxp3+ cancer cells.
Conclusions: Extrahepatic biliary cancers are often accompanied by the significant infiltration of IgG4+ cells and IgG4 reaction in biliary cancers might be associated with the evasion of the tumor-related immune surveillance. Moreover, cancer cells could play a role of regulatory functions by themselves directly and indirectly via a production of IL-10.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 236, Tuesday Afternoon