Mesothelin‑specific T cell cytotoxicity against triple negative breast cancer is enhanced by 40s ribosomal protein subunit 3‑treated self‑differentiated dendritic cells.

Abstract

Triple negative breast cancer (TNBC) lacks targeted treatment resulting in poor prognosis. Targeting overexpressing mesothelin (MSLN) using MSLN-specific T cells is an attractive treatment approach and the aim of the present study. The expression of MSLN in human TNBC paraffin sections was analyzed by immunohistochemistry. Lentiviral vector harbored 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 cell (MSLN-SmartDC) for MSLN-specific T cell activation. The results showed high MSLN in 32.8% of all breast cancer subtypes and 57% in TNBC. High MSLN was significantly associated with TNBC subtype and the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. MSLN-SmartDC exhibited comparable phenotype to DC generated by exogenous cytokine treatment and an 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 expressions 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 with parental MDA-MB-231 in both two dimensional (2D)- and 3D-culture systems. In conclusion, the results demonstrated the efficacy of MSLN-SmartDC to promote MSLN-specific T cells response against TNBC and RPS3 can enhance the cytolytic activity of these T cells providing an alternative treatment approach for patients with TNBC.