Immune microenvironment of cervical cancer and the role of IL-2 in tumor promotion.

The tumor microenvironment (TME) is a heterogeneous mixture of resident and tumor cells that maintain close communication through their secretion products. The composition of the TME is dynamic and complex among the different types of cancer, where the immune cells play a relevant role in the elimination of tumor cells, however, under certain circumstances they contribute to tumor development. In cervical cancer (CC) the human papilloma virus (HPV) shapes the microenvironment in order to mediate persistent infections that favors transformation and tumor development. Interleukin-2 (IL-2) is an important TME cytokine that induces CD8+ effector T cells and NKs to eliminate tumor cells, however, IL-2 can also suppress the immune response through Treg cells. Recent studies have shown that CC cells express the IL-2 receptor (IL-2R), that are induced to proliferate at low concentrations of exogenous IL-2 through alterations in the JAK/STAT pathway. This review provides an overview of the main immune cells that make up the TME in CC, as well as the participation of IL-2 in the tumor promotion. Finally, it is proposed that the low density of IL-2 produced by immunocompetent cells is used by tumor cells through its IL-2R as a mechanism to proliferate simultaneously depleting this molecule in order to evade immune response.

Evidence that the viral oncoproteins E6 and E7 of HPV induce the expression of a functional IL-2R on cervical cancer cells.

HPV-positive (HPV+) cervical cancer (CC) cells have been reported to express the IL-2 receptor (IL-2R) in contrast to virus-negative CC cells. This work was carried out to evaluate whether HPV infection induces IL-2R expression in CC cells. The analysis of the IL-2R expression data collected from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) using the Xena platform demonstrate a higher expression of IL-2R subunits in CC tumors in comparison with normal tissues. Moreover IL-2Rß expression is consistently higher in HPV+ tumors versus HPV- tumors. Furthermore, it was demonstrated that transfection of the HPV E6/E7 genes into the C33A (HPV-) cell line promotes IL-2R expression and regulates proliferation in response to exogenous IL-2. Additionally, we found that HPV+ cell lines enhances their proliferation in co-culture with peripheral blood lymphocytes (PBLs). To corroborate that the viral proteins E6 and E7 were related to the effects mediated by IL-2, we used cells derived from the HeLa cell line in which the expression of E6/E7 has decreased, we found that it loses the ability to respond to the exogenous IL-2 stimuli. Finally, the importance of IL-2R in CC, as an immune escape mechanism, is discussed.