# Interaction Between Mesenchymal Stromal Cells and Tumor Cells Present in Cervical Cancer Influences Macrophage Polarization

## TL;DR

Cervical cancer cells and stromal cells work together to shift macrophages toward a tumor-friendly state, boosting cancer growth.

## Contribution

This study reveals how tumor and stromal cell interactions promote M2 macrophage polarization with high immunosuppressive potential in cervical cancer.

## Key findings

- TCs and CeCa-MSCs promote M2 macrophage polarization with increased immunosuppressive activity.
- Macrophages from TC/CeCa-MSC cocultures show higher IL-4, IL-10, and IDO production compared to TC/NCx-MSC cocultures.
- TC/CeCa-MSC cocultures enhance macrophage immunosuppressive potential and reduce T lymphocyte proliferation.

## Abstract

Within tumor tissue, cancer cells communicate with the microenvironment to generate immunosuppressive cell populations that favor tumor progression. This study evaluated whether the interaction between cervical tumor cells (TCs) and mesenchymal stromal cells derived from cervical cancer (CeCa-MSCs) promotes the polarization of macrophages toward the M2 phenotype. The M2 macrophage polarization and the immunosuppressive potential of such cells were evaluated in terms of membrane markers, cytokine secretion, phagocytic capacity, the inhibition of T lymphocyte proliferation, and the generation of regulatory T cell populations. Our findings show that the interaction between TCs and CeCa-MSCs favors the M2 polarization of macrophages that show a high immunosuppressive capacity. This study suggests that cell communication between TCs and MSCs present in cervical tumors could favor tumor growth through the polarization of macrophages with high immunosuppressive potential.

Background/Objectives: Macrophages with the M2 phenotype are an immune population with great relevance for tumor development. We have previously demonstrated that mesenchymal stromal cells (MSCs) from cervical cancer (CeCa-MSCs) enhance the immunomodulatory activity of CeCa cells on T lymphocytes; however, the effect of these cells on the ability of tumor cells to polarize macrophages had not been evaluated to date. Methods: To address this, we set out to analyze the effect of normal cervix (NCx) and CeCa-MSCs interacting with CeCa tumor cells (TCs) to polarize macrophages in a coculture system. Results: Our results show that macrophages from TC/NCx-MSC cocultures decreased CD163 expression. In turn, we observed that macrophages from TC/CeCa-MSC cocultures, in contrast to those in the presence of TCs/NCx-MSCs, increased the intracellular production of IDO, IL-4, and IL-10; decreased T lymphocyte proliferation; and increased the presence of soluble IL-10. Interestingly, coculture in the presence of TCs/NCx-MSCs decreased the capacity of macrophages to generate regulatory T lymphocyte populations, as well as their phagocytic capacity, and increased IL-6 secretion, unlike the coculture of macrophages in the presence of TCs/CeCa-MSCs. Our results show that TCs/CeCa-MSCs in cocultures, unlike TCs/NCx-MSCs, have a greater capacity to polarize macrophages to an M2 phenotype and that such macrophages have a greater immunosuppressive potential. Conclusions: This in vitro study suggests that intracellular communication between MSCs and tumor cells in CeCa may promote tumor growth through the polarization of macrophages with increased immunosuppressive activity.