Abstract A094: Characterization of pancreatic cancer endothelial cells: Approach to enhance immune cell infiltration for immunotherapy

Abstract

Abstract The hurdles in realizing immunotherapy success for cure stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. We previously proposed that these phenomena are due, in part, to the deployment of tumor-associated antigens, or employment of tumor-associated endothelium acting as a gatekeeper for immune cell infiltration into the cancer tissue (Nakajima et al, Cancer Res 2017;77:5441-4). Here, an extensive study unveiled functional/molecular differences of endothelium derived from pancreatic cancer and normal pancreas. They were isolated from fresh surgical specimen by magnet-based selection. The primary culture of tumor-associated endothelial cells was confirmed by double positive expressions of endothelial markers, CD31 and ERG1. They showed the short vessel formations and the narrow area of capillary network, indicating the low potential of angiogenesis. Further, peripheral blood–derived lymphocytes were less adhering to the tumor-associated endothelial cells. To find the molecular differences, microarray analysis was performed, and identified 2748 molecules distinct from endothelial cells of noncancerous tissues (p<0.05). Then, a bioinformatic approach, i.e., ingenuity pathway analysis (IPA) reconstructed 47 pathways (p<0.05). Among them, TNFR1 signaling appeared as a highly possible pathway, which is involved in immune cell infiltration: (p=0.005, z score=2.00) with aberrantly expressed upstream molecules of the pathway. As for the downstream molecules, ICAM1 was highly expressed, whereas VCAM1 and E-selectin were generally suppressed on pathologic specimens of pancreatic cancer (n=20) as well as primary cultured tumor-associated endothelial cells. The unfulfilled expressions may be causes of noninflamed immune microenvironment of pancreatic cancer. Thus, our study highlights possible molecular candidates of tumor-associated endothelium shaping tumor microenvironment to enhance immune cell infiltration for successful immunotherapy. Citation Format: Kosei Nakajima, Yashunori Ino, Toshimitsu Iwasaki, Nobuyoshi Hiraoka. Characterization of pancreatic cancer endothelial cells: Approach to enhance immune cell infiltration for immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A094.