Abstract 320: Combined RNA nanostructure and 5FU for enhanced pancreatic cancer treatment through immunochemotherapy of targeting TAM2 deletion in TME

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most immune-resistant tumor types. Single-agent immune modulators targeting immune checkpoint blockade and multi-modal therapies including target immunotherapy have been proven to be clinically ineffective. Intensive research to explore novel targeted therapeutic strategies is undoubtedly required. Recently, nucleic acid nanotechnology has emerged as a promising approach for cancer treatment as it is highly programmable. Our previous results demonstrated that a replicable single-strand RNA origami (RNA-OG) technology stimulates a potent innate response primarily through a Toll-like receptor (TLR3) pathway to activate NK- and CD8-dependent antitumor immunity and counteract the peritoneal immunosuppressive environment in a murine peritoneal color cancer model. In this study, inspired by the robust innate immune suppressor cell types including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages M2 (TAM2) in the tumor microenvironment of pancreatic cancer, we designed a combined single-strand RNA (ssRNA) origami integrated with 5FU immunochemotherapeutic strategy to efficiently target pancreatic cancer cells and TAM in tumor microenvironments. The ssRNA is designed to fold from a long ssRNA molecule in a programmable manner. In pancreatic cancer cell lines, the ssRNA combined with 5FU significantly inhibited pancreatic cancer cell growth by growth curve and colony formation assay. We found that the combined ssRNA with 5FU dramatically induced pancreatic cancer cell death using pancreatic cell line and Raw264.7 in 2D cultures compared with 5FU. In 2D culture pancreatic cancer and Raw264.7 cell lines, 90% of the RNA origami was internalized in Raw264.7 cells within an hour. We also found that ssRNA origami triggered Raw264.7 cell death. In the xenograft model, ssRNA origami used with 5FU demonstrated high antitumor efficacy against pancreatic cancer. The Arg1 expression, which is the marker of TAM M2 and MDSC, was analyzed in xenograft tumor tissues using immunohistochemistry. We found that ssRNA implemented alongside 5FU significantly decreases the amount of Arg 1 positive TAM2 and MDSC cells in xenograft tumor tissue. We hypothesize that the ssRNA origami induced cell death of TAM M2 and MDSC cells in tumor microenvironments used alongside 5FU to target pancreatic cancer cells synergistically increases antitumor efficacy based on immunochemotherapy. Our integrated strategy is a promising approach to synergistically kill and remove the innate immune-suppressor cells in the tumor microenvironment, improving the therapeutic efficacy against pancreatic cancer. Citation Format: Yang Xu, Guangbao Yao, Chen Gong, Xiaodong Qi, Hao Yan. Combined RNA nanostructure and 5FU for enhanced pancreatic cancer treatment through immunochemotherapy of targeting TAM2 deletion in TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 320.