Análisis de la capacidad de las células estromales mesenquimales (CEM) derivadas de neoplasias cervicales (NIC y CaCu) para inducir linfocitos T reguladores.

Abstract

Cervical cancer (CC) is a public health problem in the mexican population. This disease is associated with human papilloma virus (HPV) infection, mainly HPV-16. The failure of the immune response in patients with CC has been associated, among other factors, to the persistentice of HPV-16 infection as well as with increasing amounts of T regulatory cells (Treg) CD4+CD25highFoxP3+ during malignance development. However, until now the mechanisms of their induction are unknown. On the other hand, it has been recently reported that mesenchymal stromal cells (MSC) are characterized by their immunosuppressive effects on T cells through the production of immunosuppressive factors as well as in the induction of regulatory T cell (Treg). In consequence, their presence in tumor tissues may be important to suppress the immune response against the tumor. In this study we postulated that MCS derived from cervical intraepithelial neoplasia (CIN) and CC may have the capability to induce CD4+CD25highFoxP3+CD45RO+ Treg cells. To test this hypothesis, we established co-cultures of peripheral blood mononuclear cells (PBMC) from healthy donors and patients with CC with different strains of MSC in the presence or absence of antigenic peptides (15-25mers) derived from HPV-16 E6 and E7 proteins. After four days of culture, we observed that MSC derived from cervical neoplasias (CIN and CC) were capable to induce CD4+CD25highFoxP3+ and CD4+CD25highFoxP3+CD45RO+ Treg with frequencies from 0.10 to 0.94% and from 0.03 to 0.61% respectively of the total of PBMC. While, MSC derived from normal cervix induced frequencies from 0.19 to 0.76% and from 0.07 to 0.19% respectively. In all cases the induction of CD4+CD25highFoxP3+CD45RO+ Treg was strongly associated with the presence of HPV-16 E6 and E7 antigenic peptides into the cell cultures. On the other hand, the addition of anti-CD3/CD28 antibodies to the cell cultures strongly increased the frequency of Treg and this induction was independent of the presence of HPV-16 E6 and E7 antigenic peptides. Finally, the suppressive capability of the Treg induced in these cell cultures (PBMC-iTreg) was performed in inhibitory PBMC proliferation assays and it was correlated with the frequencies of the Treg found in the cell cultures. These results suggest that tumor derived MSC and the presence of HPV-16 E6 and E7 antigens may play and important role in the induction of Treg.