Monocytes Provoke Breast Cancer Cells to Express PD-L1 via a Cell-to-Cell Interaction Involving CD44 and Moesin.

Abstract

Abstract: Triple-negative breast cancers (TNBCs), especially metastatic recurrent TNBCs, have a poorer prognosis than many other breast cancers. In recent years, immunotherapy using immune checkpoint inhibitors has been conducted for TNBC patients. Although a limited proportion of patients show excellent response, about half of the patients do not significantly respond to the immunotherapy. Monocytes are the progenitors of macrophages that are most abundantly seen in the tumor microenvironment (TME), but the influence of monocytes on breast cancer cells (BCCs) has not been fully clarified. Thus, we examined whether monocytes prompted BCCs to express PD-L1. As results, BCCs expressed higher levels of PD-L1 and its mRNA after co-culture with monocytes. RNA sequencing analysis revealed overexpression of Moesin mRNA in the BCCs co-cultured with monocytes. siRNA-mediated knockdown of Moesin restored the increase in PD-L1 expression. An addition of CD44 antibody canceled the augmentation of PD-L1 expression caused by the co-culture, suggesting that Moesin and CD44 may be essentially involved in the cell-to-cell interaction between monocytes and BCCs to induce PD-L1 expression. These findings may suggest a novel machinery of tumor escape from anti-tumor immunity, potentially providing implications for improving immunotherapy against TNBCs that are resistant to current immune checkpoint blockade therapy.