Abstract 2739: Genetic modification of mesothelial cells with full length membrane-bound TRAIL for ovarian cancer treatment
Authors: Yue Er , Walser Tonya , Mirzapoiazova Tamara , Salgia Ravi , Wang Edward W. 
Published: June 2023

Mesothelial cells lining the peritoneum play an important role in epithelial ovarian cancer (EOC) locoregional spreading by promoting cancer cell proliferation, adhesion, and invasion into the peritoneal wall and organs. Peritoneal dissemination represents a critical first step in EOC progression, and we posit that genetic modification of mesothelial cells with full length membrane-bound TRAIL is a practical approach to intervention and will provide local control of EOC progression. Here, we stably overexpressed full length tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with a lentiviral vector in the immortalized mesothelial cell line, MeT5A. Overexpression of TRAIL on the cell surface of MeT5A was confirmed by flow cytometry, and no obvious changes in proliferation or morphology were observed when MeT5A/TRAIL cells were grown in culture. In co-culture experiments, however, MeT5A/TRAIL cells induced apoptosis of surrounding cancer cells and continued proliferating until the culture surface was confluent with mesothelial cells alone. Interestingly, MeT5A/TRAIL not only induced cell death of TRAIL-sensitive cancer cells, such as OVCAR3 and H460, but it also induced significant apoptosis of cancer cells previously deemed resistant to soluble TRAIL, such as A2780, and OVCAR8. This finding suggests that full length TRAIL (amino acid 1-281) expressed on the cell surface is capable of activating death receptor-mediated apoptotic pathways that are not reactive to the soluble form of TRAIL (amino acid 114-281), which was previously developed as a cancer therapeutic and thoroughly evaluated in animal models and clinical trials. When co-cultured with MeT5A/TRAIL, primary ovarian cancer cells from patients also underwent apoptosis as detected by flow cytometry and the upregulation of cleaved caspase-3, caspase-8, caspase-9, PARP, and Bid on Western blots. Next, we assessed the anticancer potential of mesothelial cells expressing membrane-bound TRAIL in a NSG xenograft mouse model of ovarian cancer. Intraperitoneal inoculation of MeT5A/TRAIL cells significantly reduced overall cancer burden in mice where OVCAR3, A2780, and OVCAR8 cancer cells were pre-established. Intraperitoneal gene delivery of TRAIL to resident peritoneal mesothelial cells utilizing a conditionally replicative adenovirus vector also prolonged survival of NSG mice bearing A2780 xenografts. Our data suggest that genetic modification of mesothelial cells with full length membrane-bound TRAIL is feasible and has therapeutic potential for disrupting EOC progression.

Citation Format: Er Yue, Tonya Walser, Tamara Mirzapoiazova, Ravi Salgia, Edward W. Wang. Genetic modification of mesothelial cells with full length membrane-bound TRAIL for ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2739.