Abstract A092: Mesenchymal Stem Cells Shaping the Tumor Microenvironment in Metastatic PDAC: a Step Towards Clinical Translation

Abstract Background: Metastatic PDAC presents a dire prognosis and high chemoresistance, linked partly to the complex tumor microenvironment (TME). In this context, mesenchymal stem cells (MSCs) represent a promising strategy for drug delivery, given their capacity to uptake drugs and target tumors remodeling the tumor microenvironment. MSCs can promote immune cell infiltration, contribute to breaking tumor-induced immunotolerance and create a less supportive environment for tumor growth. This study aims to investigate the therapeutic effects of a MSC-based therapy for the delivery of nab-paclitaxel (n-PTX) in preclinical models of metastatic PDAC. Methods: Liver metastases were induced by injecting the K8484 cell line into the portal vein of C57BL/6N mice. At day 20 after tumor induction, metastatic mice were intraportally injected with syngeneic MSCs. MSC biodistribution was studied by IVIS, RT-PCR and confocal microscopy. MSCs were in vitro loaded with n-PTX and drug uptake was evaluated using 2P microscopy, LC/MS-MS analysis and TEM. MSCs loaded with n-PTX were administered to mice with established tumors. Metastatic growth was monitored by MRI and toxicity was assessed through biochemical analysis. The immune infiltrate was analyzed in both the tumor and the entire liver using flow cytometry and IHC. The same experimental setup was applied using allogeneic or human MSCs across different preclinical models. Results: RT-PCR and IVIS revealed a liver accumulation of MSCs. In the immunocompetent models, n-PTX-loaded MSCs reported a significant metastatic reduction compared to mice treated with not-loaded MSCs or not-treated mice. A lower hematological toxicity was reported using n-PTX-loaded MSCs, compared to free n-PTX. The infusion of MSCs, both syngeneic and allogeneic, induced a significant increase in the CD3+ cells within the TME compared to controls, and bulk RNAseq analysis post MSCs + n-PTX injection demonstrated an enrichment in several pathways linked to anti-tumor immunity. Notably, treatment with syngeneic MSCs reduced macrophage infiltration in the TME, whereas allogeneic MSC infusion led to their increase. The treatment with human MSCs induced a significant reduction of metastatic growth in NSG mice. Conclusion: A novel approach employing MSCs to deliver n-PTX for metastatic PDAC treatment was developed and assessed in preclinical models. This study offers valuable insights for potential translation into human clinical trials. Notably, drug-loaded MSCs have been efficiently manufactured under Good Manufacturing Practice conditions, ensuring the feasibility of clinical translation. The findings of this study hold the promise of advancing personalized medicine and utilizing the capabilities of MSCs and the tumor microenvironment to enhance clinical outcomes. Citation Format: Benedetta Ferrara, Paolo Riccardo. Camisa, Valeria Lanci, Alessia Solcia, Antonio Citro, Aisha Rizzetto, Valentina Coccè, Chiara Gnasso, Andrea Annoni, Augusto Pessina, Stefano Crippa, Lorenzo Piemonti. Mesenchymal Stem Cells Shaping the Tumor Microenvironment in Metastatic PDAC: a Step Towards Clinical Translation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A092.