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.
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.
Laboratorio de Inmunología y Cáncer, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico; Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, D.F., Mexico.
R
R
García-Rocha
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, D.F., Mexico.
M
M
Moreno-Lafont
Laboratorio de Inmunobiología FES-Zaragoza, UNAM, México, D.F., Mexico.
M L
ML
Mora-García
Laboratorio de Inmunobiología FES-Zaragoza, UNAM, México, D.F., Mexico.
B
B
Weiss-Steider
Laboratorio de Células Troncales Mesenquimales, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico.
J J
JJ
Montesinos
Laboratorio de Oncología Molecular, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico.
P
P
Piña-Sánchez
Laboratorio de Inmunología y Cáncer, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico; Laboratorio de Inmunobiología FES-Zaragoza, UNAM, México, D.F., Mexico. Electronic address: albertomon@yahoo.com.
A
A
Monroy-García
D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
D017077:Culture Media, Conditioned; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10
Cervical cancer; Interleukin-10; Major histocompatibility complex class I antigens; Mesenchymal stromal cells; Transforming growth factor beta