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

Abstract

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.

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

“…Several studies have analyzed PD-L1 expression in CSCs. [33][34][35] In the present study, flow cytometry analysis revealed that PD-L1 expression was greater in GL261-derived neurospheres than in GL261 cells (Fig. 4d).…”

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Optimizing poly (ADP‐ribose) polymerase inhibition through combined epigenetic and immunotherapy

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“…Hugo et al 41 TA B L E 4 Potential pathways and therapeutic strategies against cancer stem cells (CSCs) correlation between the stemness score of the breast cancer and PD-L1 levels. 43 Furthermore, PD-L1 knockdown decreased expression of embryonic stem cell transcription factors like octamerbinding transcription factor-4A, Nanog, and the stemness factor BMI1. Wnt signaling might also be associated with PD1i resistance, and Wnt is a crucial pathway in EMT and CSC formation.…”