PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation

Int J Cancer. 2017 Oct 1;141(7):1402-1412. doi: 10.1002/ijc.30834. Epub 2017 Jun 30.


The expression of PD-L1 in breast cancer is associated with estrogen receptor negativity, chemoresistance and epithelial-to-mesenchymal transition (EMT), all of which are common features of a highly tumorigenic subpopulation of cancer cells termed cancer stem cells (CSCs). Hitherto, the expression and intrinsic role of PD-L1 in the dynamics of breast CSCs has not been investigated. To address this issue, we used transcriptomic datasets, proteomics and several in vitro and in vivo assays. Expression profiling of a large breast cancer dataset (530 patients) showed statistically significant correlation (p < 0.0001, r = 0.36) between PD-L1 expression and stemness score of breast cancer. Specific knockdown of PD-L1 using ShRNA revealed its critical role in the expression of the embryonic stem cell transcriptional factors: OCT-4A, Nanog and the stemness factor, BMI1. Conversely, these factors could be induced upon PD-L1 ectopic expression in cells that are normally PD-L1 negative. Global proteomic analysis hinted for the central role of AKT in the biology of PD-L1 expressing cells. Indeed, PD-L1 positive effect on OCT-4A and Nanog was dependent on AKT activation. Most importantly, downregulation of PD-L1 compromised the self-renewal capability of breast CSCs in vitro and in vivo as shown by tumorsphere formation assay and extreme limiting dilution assay, respectively. This study demonstrates a novel role for PD-L1 in sustaining stemness of breast cancer cells and identifies the subpopulation and its associated molecular pathways that would be targeted upon anti-PD-L1 therapy.

Keywords: AKT; Nanog; OCT4A; PD-L1; breast cancer; cancer stem cells; stemness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / metabolism
  • B7-H1 Antigen / physiology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Down-Regulation
  • Female
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Nanog Homeobox Protein / metabolism*
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / physiology
  • Octamer Transcription Factor-3 / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Polycomb Repressive Complex 1 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-akt / physiology*
  • Transplantation, Heterologous


  • B7-H1 Antigen
  • BMI1 protein, human
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • Polycomb Repressive Complex 1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt