LAUSR

Introduction: We have previously identified C4b-binding protein α-chain (C4BPA) as a serum biomarker for pancreatic ductal adenocarcinoma (PDAC). Serum C4BPA level was significantly higher, especially in the early stage of PDAC patients, than in healthy controls as well as in patients with pancreatitis and other malignancies (Br J Cancer 2016). C4BPA is known as a potent soluble inhibitor of the complement system; however, the functional role of C4BPA remains unknown during tumor progression. In this study, we investigated the clinical significance of C4BPA expression and explored the possibility of correlation between C4BPA and antitumoral immunity in PDAC progression. Materials and Methods: Immunohistochemistry (IHC) for C4BPA was performed in resected PDAC tissues. PDAC tissues were obtained from 172 consecutive patients who underwent pancreatectomy at the Department of General Surgery, Chiba University Hospital, Japan from January 2011 to December 2014. In in vitro experiments, we evaluated C4BPA expression in human pancreatic duct epithelial (HPDE) cell, 7 human PDAC cell lines, resected PDAC sample, and the adjacent normal pancreatic tissues. C4BPA is known as a soluble inhibitor of the complement system and an activating ligand for CD40, which alters tumor microenvironment. The binding of CD40 on B cells or macrophages activates antitumoral T cells and antigen-presenting cells and induces a variety of downstream effects. To elucidate the molecular mechanism, we have addressed the association between C4BPA and CD40 expression in PDAC cells. Results: In IHC analysis, we found that C4BPA was mainly expressed in the stroma surrounding PDAC cells. Based on the staining intensity, PDAC samples were categorized into two groups: 75 cases as a high-expression group and 97 cases as a low-expression group. The Kaplan-Meier analysis showed that patients with low C4BPA expression presented a significantly shorter disease-free (P=0.011) and overall survival time than those with high C4BPA expression (P=0.0016, log-rank test). On multivariate analyses, high venous invasion and low C4BPA expression were observed as an independent prognostic factor in patients with PDAC after curative surgery. In in vitro experiment, C4BPA was strongly expressed in human pancreatic duct epithelial (HPDE) cell line but not in PDAC cell lines by Western blotting. Now, we have confirmed C4BPA expression in frozen section of PDAC tissues and the adjacent normal pancreas tissues, and CD40 expression in various PDAC cell lines. Discussion: Our results suggested that low C4BPA expression in the stroma of PDAC is associated with unfavorable prognosis of PDAC patients. These results also suggested that C4BPA might play a role in the process of elimination and equilibrium phase based on the immunoediting theory. Citation Format: Kosuke Sasaki, Shigetsugu Takano, Hideyuki Yoshitomi, Kazuyuki Sogawa, Shingo Kagawa, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Daisuke Suzuki, Nozomu Sakai, Takashi Mishima, Eri Nakadai, Masayuki Ohtsuka. C4BPA identified as a novel biomarker is associated with favorable outcome of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C64.