Abstract 2740: Effect of pancreatic cancer cell derived extracellularvesicles on the tumor microenvironment

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one amongst the most lethal malignancies, with a 5 year survival rate of <10%.While the tumor microenvironment in PDAC is highly immunosuppressive, little is known about the mechanisms of immune invasion leading to rapid tumor progression. Hence, in-depth exploration of early cellular and molecular drivers of PDAC is desirable for early and precise diagnosis and to identify new biological targets for developing new therapies. Extracellular vesicles (EVs) are nanometer sized particles that are shed by most tissues/organs and are known to be important mediators of intercellular signaling and molecular transfer. We hypothesized that pancreatic cancer derived EVs may play an important role in mediating the interactions among the tumor and surrounding microenvironment (TME). Given that tumor-associated macrophages (TAMs) are integral components of the TME that can promote tumor progression, tumor invasion, and intravasation to other parts of the body, this study is focused on investigating the role of PDAC derived EVs in macrophages polarization, which in turn would impact tumor cell proliferation and invasion. Results: EVs were isolated from 6 pancreatic cancer (PaCa) and 2 normal established pancreatic epithelial cell lines. EVs were characterized using nanoparticle tracking (NTA) and immunoblot analysis. LC-MS/MS based shotgun proteomics analyses of EVs revealed that PaCa cell line derived EVs were significantly enriched in potentially immunomodulatory proteins such as S100 calcium-binding protein A4 (S100A4) and human leukocyte antigen-B (HLA-B). However, PaCa cell EVs had significantly less MHC-class-I-related chain A (MICA), a protein important for proper human leukocyte antigen (HLA) function, as compared to normal pancreatic epithelial cell derived EVs. These data suggest that PaCa derived EVs may influence immunomodulation and macrophage function within the tumor microenvironment thereby strengthening our hypothesis. Further experimental studies aimed at delineating the precise mechanism of action of EVs in macrophage polarization is ongoing. Conclusions: Our finding suggests significant difference among the molecular composition of PaCa derived cargos as compared to and normal cells derived EVs that could be useful in furthering our understanding about pancreatic cancer etiology. Furthermore, the novel insights obtained from these studies may augment the development of biomarkers that can be used for early detection of the disease and improved therapeutics to improve clinical outcomes. Citation Format: Baldev Singh, Charles Hinzman, Edina Wang, Anton Iliuk, Jose Trevino, Keith Unger, Partha Banerjee, Amrita K. Cheema. Effect of pancreatic cancer cell derived extracellularvesicles on the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2740.