Impact of epithelial to mesenchymal transition on the regulation of anti-tumour immune response in breast cancer

Malina Xiao

Research output: Types of ThesisDoctoral Thesis

Abstract

Epithelial to mesenchymal transition (EMT) is well-known mechanism which is associated with poor prognosis and tumor escape from immune escape surveillance in cancer. In addition to the transcriptional regulation of PD-L1 in breast cancer (BC) undergoing EMT, here we show that CMTM6 is overexpressed in EMT-activated BC cells as compared with epithelial cells. CMTM6 was recently consider as a key regulator for the stabilization and recycling of PD-L1 at the cell surface in a broad range of cancer types. We, therefore silenced CMTM6 and observed a partial but significant downregulation of surface PD-L1 in BC undergoing EMT. Further investigations demonstrate that other members of the CMTM family contribute to PD-L1 regulation. In addition to CMTM6, CMTM3 and CMTM7 were also found to be upregulated in EMT-induced BC cells. However only CMTM7 silencing modulate the SNAI-induced PD-L1 surface expression as compared with control cells. Dual CMTM6 and CMTM7 silencing significantly reduced for up to 50% the expression of the SNAI-dependent PD-L1 surface expression in mesenchymal tumor cells.Supplementary results showed that hypoxia, a common feature observed in the tumor microenvironment, positively regulated CMTM6 gene expression in several cancer cell lines. Moreover, preliminary data show that CMTM7, but not CMTM6 is transcriptionally regulated by SNAI1, but not ZEB1 in EMT-activated BC cells. Our data also suggest that targeting CMTM6 and/or CMTM7 were able to increase T cell survival by caspase3/7 measurement activity, to the same degree as PD-1/PD-L1 blockade in vitro.Overall, our results provided additional highlight EMT as new inducers of the CMTM family expression in BC as well as a comprehensive overview on PD-L1 regulation during EMT and its impact on T-cell mediated cell death via CMTM6 and CMTM7 expression.
Original languageEnglish
Supervisors/Advisors
  • Janji, Bassam, Supervisor
Publisher
Publication statusPublished - 16 Nov 2021

Keywords

  • EMT
  • Immune-checkpoints
  • CMTM family member
  • Breast cancer

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