CXCL17 and ICAM2 Are Associated With a Potential Anti-Tumor Immune Response in Early Intraepithelial Stages of Human Pancreatic Carcinogenesis

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 140; no. 1; pp. 310 - 321.e4
• Main Authors: Hiraoka, Nobuyoshi, Yamazaki–Itoh, Rie, Ino, Yoshinori, Mizuguchi, Yasunori, Yamada, Tesshi, Hirohashi, Setsuo, Kanai, Yae
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2011
• Subjects: Abscess - immunology; Abscess - pathology; Abscess - surgery; Adenocarcinoma, Mucinous - immunology; Adenocarcinoma, Mucinous - pathology; Adenocarcinoma, Mucinous - surgery; Adenocarcinoma, Papillary - immunology; Adenocarcinoma, Papillary - pathology; Adult; Aged; Animals; Antigens, CD - immunology; Carcinoma in Situ - immunology; Carcinoma in Situ - pathology; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - pathology; Cell Adhesion Molecules - immunology; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - pathology; Chemokine; Chemokine CCL17 - immunology; Danger Signal; Dendritic Cells - immunology; Female; Gastroenterology and Hepatology; Gene Expression Profiling; Humans; Immunologic Surveillance; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - pathology; Male; Mice; Mice, Inbred BALB C; Middle Aged; Multistep Carcinogenesis; Neoplasm Staging; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Pseudocyst - immunology; Pancreatic Pseudocyst - pathology; Pancreatitis, Chronic - immunology; Pancreatitis, Chronic - pathology; Precancerous Conditions - immunology; Precancerous Conditions - pathology; Premalignant Lesion; Retrospective Studies; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology; intraductal papillary mucinous adenoma; Premalignant Lesion; LFA-1; CXCL17; ICAM2; IPMN; intraductal papillary mucinous neoplasm; Multistep Carcinogenesis; intercellular adhesion molecule 2; Chemokine; Danger Signal; Langerhans cell; DC-SIGN; dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; chemokine (C-X-C motif) ligand 17; intraductal papillary mucinous carcinoma; LC; PanIN; IPMA; lymphocyte function-associated antigen 1; pancreatic intraepithelial neoplasm; dendritic cell; DC; IPMC
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2010.10.009

Background & Aims Anti-tumor immunity changes over the course of tumor progression; it is not clear how or when the developing tumor overcomes immune surveillance. Intraductal papillary mucinous neoplasm (IPMN) is an intraepithelial precursor lesion of pancreatic cancer that progresses from adenoma to carcinoma. We investigated when and how the human anti-tumor immune reaction changes during pancreatic tumor development. Methods Using immunohistochemical analysis of cells isolated from patients with IPMN, the numbers of tumor-infiltrating lymphocytes and dendritic cells and the maturation state of dendritic cells in the regional lymph nodes were investigated during tumor progression. Gene expression profiles were compared among epithelial neoplastic cells at each stage of tumor development. Biological functions of the selected gene products were analyzed using syngeneic mouse models. Results The anti-tumor immune reaction changed from an immune response to immune tolerance between the stages of intraductal papillary mucinous adenoma (IPMA) and intraductal papillary mucinous carcinoma (IPMC). Chemokine (C-X-C motif) ligand 17 (CXCL17) and intercellular adhesion molecule 2 (ICAM2) were involved in immune surveillance during tumor development—their expression levels were up-regulated exclusively in IPMA and disappeared from IPMC. CXCL17 and ICAM2 induced infiltration and accumulation of the tumor epithelial layer by immature myeloid dendritic cells. This was followed by a cellular immune reaction and ICAM2 simultaneously promoted the susceptibility of the tumor cells to cytotoxic T-cell−mediated cytolysis. These processes had a synergistic effect to increase the anti-tumor immune response. Conclusions Immune surveillance occurs during the early intraepithelial stages of human pancreatic carcinogenesis and is mediated by expression of CXCL17 and ICAM2.