Mesothelin-Specific T Cell Cytotoxicity Against Triple Negative Breast Cancer Is Enhanced By 40s Ribosomal Protein Subunit 3-Treated Self-Differentiated Dendritic Cells
Abstract Purpose Triple negative breast cancer (TNBC) is deficient in targeted treatment resulting in poor prognosis. Targeting overexpressed mesothelin (MSLN) using MSLN-specific T cells is an attractive treatment approach.Methods The immunohistochemistry of MSLN in TNBC tissues were performed. A lentiviral vector harboring granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4 (IL-4) and MSLN cDNAs was constructed to generate self-differentiated myeloid-derived antigen-presenting-cells reactive against tumor expressing MSLN dendritic cells (MSLN-SmartDC) for MSLN-specific T cell activation. The antigen specificity and cancer killing of activated T cells were accessed.Results The high expression of MSLN was found in 32.8% all breast cancer subtypes and 57% in TNBC. High MSLN was significantly associated with the TNBC subtype and the absence of ER, PR and HER2. MSLN-SmartDC exhibited comparable phenotype to DC generated by exogenous cytokine treatment; addition of 40s ribosomal protein subunit 3 (RPS3), a toll-like receptor 4 ligand, enhanced DC maturation and function by upregulation of CD40, CD80 and CD83 expression and IL-12p70 secretion. MSLN-specific CD8+CD69+ IFN-γ+ T cells were detected in T cells activated by both MSLN-SmartDC and RPS3-MSLN-SmartDC. MSLN-specific T cells activated by these DCs showed more specific killing capability against naturally expressed MSLN-HCC70 and artificially MSLN-overexpressing MDA-MB-231 compared to parental MDA-MB-231 in both 2 dimensional (2D)- and 3D-culture systems. Conclusion High MSLN was observed in TNBC patients, a potential target for TNBC treatment. MSLN-SmartDC could promote MSLN-specific T cell response against TNBC and RPS3 can enhance the cytolytic activity of these T cells providing an alternative treatment approach for TNBC patients.