Mesenchymal stromal cells derived from cervical cancer tumors induce TGF-β1 expression and IL-10 expression and secretion in the cervical cancer cells, resulting in protection from cytotoxic T cell activity

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2015-12, Vol.76 (2), p.382-390
• Main Authors: García-Rocha, R., Moreno-Lafont, M., Mora-García, M.L., Weiss-Steider, B., Montesinos, J.J., Piña-Sánchez, P., Monroy-García, A.
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cervical cancer; Coculture Techniques; Culture Media, Conditioned; Female; Humans; Interleukin-10; Interleukin-10 - metabolism; Major histocompatibility complex class I antigens; Mesenchymal stromal cells; Mesenchymal Stromal Cells - pathology; T-Lymphocytes, Cytotoxic - immunology; Transforming growth factor beta; Transforming Growth Factor beta1 - metabolism; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2015.09.001

•Cocultures of CeCa–MSCs, NCx–MSCs or BM–MSCs with CeCa cells were performed.•Only CeCa–MSCs strongly induced the expression of TGF-β1 and IL-10 production by CeCa cells.•Anti-TGF-β1 inhibited the production of IL-10 by CeCa cells in the coculture with CeCa–MSCs.•HLA-I downregulation and protection from lysis by specific CTLs by CeCa–MSCs were also observed for CeCa cells.•Anti-TGF-β and anti-IL-10 abolished HLA-I downregulation and the protection from CTL lysis.•CeCa–MSCs may protect tumor cells from immune recognition by specific CTLs via TGF-β1 and IL-10. Cervical cancer (CeCa) tumors are characterized by increased expression of TGF-β1 and IL-10, which are correlated with downregulated expression of major histocompatibility complex class I antigens (HLA-I) on cancer cells and a reduced immune response mediated by cytotoxic T lymphocytes (CTLs). Mesenchymal stromal cells (MSCs) are important components in the tumor microenvironment that have been suggested to contribute to cancer progression through the induction of TGF-β1 and IL-10. In this study, we provided evidence that MSCs derived from cervical tumors (CeCa–MSCs) cocultured with CeCa cells induced significant expression of TGF-β1 and secretion of IL-10 by CeCa cells compared to MSCs derived from the normal cervix (NCx–MSCs) and normal bone marrow (BM–MSCs; gold standard). This increase in expression was associated with a significant downregulation of HLA-I molecules and protection of the cells against specific CTL lysis. Interestingly, the addition of the neutralizing antibody anti-TGF-β to the CeCa/CeCa–MSCs coculture strongly inhibited the expression and production of IL-10 by CeCa cells. Anti-TGF-β as well as anti-IL-10 also abolished HLA-I downregulation, and reversed the inhibition of CTL cytotoxicity. These results provide evidence that TGF-β1 and IL-10 could play an important role in the downregulation of HLA-I molecules on CeCa cells induced by tumor MSCs. Our findings suggest a novel mechanism through which MSCs may protect tumor cells from immune recognition by specific CTLs.