Track: Formulation and Delivery - Biomolecular - Drug Delivery - Extended Release (Non-implant)
Category: Poster Abstract
Locally Trapping the CCL2 by Gene Delivery Nanoparticles Remodeled the Immunosuppressive Tumor Microenvironment and Inhibit Tumor Progression in Triple-Negative Breast Cancer
Purpose: Adipocyte is the most predominant resident cell in the breast cancer tumor microenvironment and plays a vital role in cancer progression, yet the underlying mechanisms and functional mediators remain elusive. Those adipocytes are defined as cancer associated adipocyte (CAA). In this work, we first examined the highly expressed gene in CAA is CCL2 (C-C Motif Chemokine Ligand 2) with experimental analysis and mathematical validation. Further analysis suggested that CCL2 is the key mediator in immunosuppressive tumor microenvironment in 4T1 triple negative breast cancer model. We then designed a tumor-targeted, locally expressed, non-viral nanoparticle mediated gene therapy (pCCL2 trap) to block CCL2 signaling within the tumor microenvironment. Compared with commercial available CCL2 monoclonal antibody, our strategy exhibited a proved PK/PD profile, increased the CCL2 antibody accumulation within the tumor microenvironment, decreased the tumor growth and facilitated the PD-L1 based checkpoint blockade immunotherapy. Methods: Patients tumor sample and survival data were obtained from TCGA database. Kaplan-Meier survival curve was plotted by R. A full understanding of the cross-talk between CAA and breast cancer cells were achieved by in vitro co-cultured mature adipocyte with breast cancer cells in trans-well system. Cationic lipid and anionic polymer were used to construct the CCL2 trap nanoparticles. The tumor volume changes in the study were measured by caliper. The changes in tumor microenvironment were characterized by flow cytometry, immunofluorescence staining, Masson Trichrome staining and real-time PCR. Results: In vitro trans-well assay suggested that CCL2 is highly expressed in CAA. In vivo experiment suggested that highly expressed CCL2 in tumor microenvironment significantly increased recruitment of M2 macrophage and MDSC, lowered the infiltration of T cells and facilitated 4T1 tumor progression. We successfully formulated the CCL2 trap nanoparticle for gene therapy in a tumor targeted-manner. Compared with the commercial available CCL2 monoclonal antibody, our strategy increased the CCL2 trap antibody expression within the tumor microenvironment, prolonged the half-time of CCL2 trap antibody and decreased the tumor progression. In addition, real-time PCR, flow cytometry and immunostaining analysis revealed that our strategy remodeled the immunosuppressive tumor microenvironment, increased the T cell infiltration and further facilitated the PD-L1 based checkpoint blockade immunotherapy. Conclusion: In conclusion, our strategy successfully provided a tumor-targeted gene therapy for triple negative breast cancer.