Epithelial to Mesenchymal Transition Regulates Surface PD-L1 via CMTM6 and CMTM7 Induction in Breast Cancer

Simple Summary Epithelial to mesenchymal transition (EMT) is a mechanism endowing tumor cells with aggressive properties and escape immune surveillance. Here, we reported that activating EMT process in breast cancer cells upregulates CMTM6, an essential protein required for cell surface expression of PD-L1. In addition to CMTM6, our in silico data on triple negative breast cancer patients showed a positive correlation between EMT markers and two other members of CMTM family (CMTM3 and CMTM7). These results were validated in EMT-inducible MCF-7 model that exhibited a downregulation of cell surface expression of PD-L1 by dual targeting CMTM6 and CMTM7. Considering the prominent role of PD-L1 in tumor immune evasion, our study provides an additional clue on how PD-L1 is regulated in aggressive breast cancer cells and pave the way to assess the therapeutic benefit of EMT inhibitors in combination with anti PD-L1 blockade in highly aggressive breast cancer patients. CMTM6 is a critical regulator of cell surface expression of PD-L1 in tumor cells, but little is known about the transcriptional regulation of CMTM6. Here we report that the expression of CMTM6 positively correlates with the epithelial to mesenchymal transition (EMT) score in breast cancer cell lines and with the major EMT marker Vimentin in triple-negative breast cancers (TNBC). We showed that CMTM6 is concomitantly overexpressed with PD-L1 in breast mesenchymal compared with the epithelial cells. Driving a mesenchymal phenotype in SNAI1-inducible MCF-7 cells (MCF-7(Mes) cells) increased both PD-L1 and CMTM6. CMTM6 silencing in MCF-7(Mes) cells partially reduced cell surface expression of PD-L1, indicating that a proportion of the PD-L1 on the surface of MCF-7(Mes) cells depends on CMTM6. We also found a positive correlation between CMTM3 and CMTM7 expression with EMT score in breast cancer cells, and with Vimentin in TNBC patients. Dual knockdown of CMTM6 and CMTM7 significantly decreased PD-L1 surface expression in MCF-7(Mes) cells, indicating that both CMTM6 and CMTM7 regulate the expression of PD-L1. This study highlights the importance of CMTM6 and CMTM7 in EMT-induced PD-L1 and suggests that EMT, CMTM6 or CMTM7 modulators can be combined with anti-PD-L1 in patients with highly aggressive breast cancer.

Automated summary

This study highlights the importance of CMTM6 and CMTM7 in regulating PD-L1 expression in aggressive breast cancer cells. Activating EMT process in breast cancer cells upregulates CMTM6, which is essential for cell surface expression of PD-L1. Dual targeting CMTM6 and CMTM7 can decrease PD-L1 surface expression, suggesting potential therapeutic benefits in highly aggressive breast cancer patients.