Polyphenols Modulating Effects of PD-L1/PD-1 Checkpoint and EMT-Mediated PD-L1 Overexpression in Breast Cancer

Abstract

Investigating dietary polyphenolic compounds as antitumor agents are rising due to the growing evidence of the close association between immunity and cancer. Cancer cells elude immune surveillance for enhancing their progression and metastasis utilizing various mechanisms. These mechanisms include the upregulation of programmed death-ligand 1 (PD-L1) expression and Epithelial-to-Mesenchymal Transition (EMT) cell phenotype activation. In addition to its role in stimulating normal embryonic development, EMT has been identified as a critical driver in various aspects of cancer pathology, including carcinogenesis, metastasis, and drug resistance. Furthermore, EMT conversion to another phenotype, Mesenchymal-to-Epithelial Transition (MET), is crucial in developing cancer metastasis. A central mechanism in the upregulation of PD-L1 expression in various cancer types is EMT signaling activation. In breast cancer (BC) cells, the upregulated level of PD-L1 has become a critical target in cancer therapy. Various signal transduction pathways are involved in EMT-mediated PD-L1 checkpoint overexpression. Three main groups are considered potential targets in EMT development; the effectors (E-cadherin and Vimentin), the regulators (Zeb, Twist, and Snail), and the inducers that include members of the transforming growth factor-beta (TGF-β). Meanwhile, the correlation between consuming flavonoid-rich food and the lower risk of cancers has been demonstrated. In BC, polyphenols were found to downregulate PD-L1 expression. This review highlights the effects of polyphenols on the EMT process by inhibiting mesenchymal proteins and upregulating the epithelial phenotype. This multifunctional mechanism could hold promises in the prevention and treating breast cancer.

Keywords: Epithelial-to-Mesenchymal Transition; breast cancer; polyphenols; programmed death-ligand 1; triple-negative breast cancer.

Figure 1

Tumor-intrinsic PD-L1 signaling in cancer initiation and development. The diagram highlights downstream signaling of PD-L1 activation in cancer. Hypoxia-inducible factors, HIF; interferon regulatory factor1, IRF1; MYC proto-oncogene, bHLH transcription factor, Myc; Janus kinase, JAK; signal transducer and activator of transcription (STAT)1/3; nuclear factor-kappa B, NF-ƙB; bromodomain-containing protein 4, BRD4; interferon-gamma, IFN-γ; IFN-γ receptor 1/2, IFNGR1/2; phosphoinositide 3-kinase, PI3K; protein kinase B, AKT; mammalian target of rapamycin, mTOR; extracellular-signal-regulated kinase, ERK; mitogen-activated protein kinase, MEK; B-Raf Serine/Threonine-Protein, BRAF; rat sarcoma, Ras; epidermal growth factor, EGF; hepatocyte growth factor HGF; programmed death-ligand 1, PD-L1.

Figure 2

PD-L1-mediated EMT stimulation. The diagram highlights the downstream signaling of EMT in cancer. Interferon-gamma, IFN-γ; IFN-γ receptor 1/2, IFNGR1/2; epidermal growth factor, EGF; hepatocyte growth factor HGF; Janus kinase, JAK; signal transducer and activator of tran-scription3, STAT3; nuclear factor-kappa B, NF-ƙB; phosphoinositide 3-kinase, PI3K; protein kinase B, AKT; mammalian target of rapamycin, mTOR; zinc finger E-box binding homeobox 1/2, Zeb1/2; Snail family transcriptional repressor 1, Snail 1; extracellular-signal-regulated kinase, ERK; mitogen-activated protein kinase, MEK; B-Raf Serine/Threonine-Protein, BRAF; rat sarcoma, Ras; programmed death-ligand 1, PD-L1; transforming growth factor-beta, TGF-β; mothers against decapentaplegic, Smad; epithelial-mesenchymal transition, EMT.

Figure 3

The mechanism of curcumin-mediated programmed death-ligand 1 (PD-L1) inhibition in breast cancer cells. Signal transducer and activator of transcription, STAT; Janus kinase, JAK; nuclear factor-kappa β, NF-ƙB; smoothened, frizzled class receptor, Smo; interferon-gamma, IFN-γ; Phosphoinositide 3-kinase, PI3K; protein kinase β, AKT; mammalian target of rapamycin, mTOR; mitogen-activated protein kinase, MAPK; B-raf serine/threonine-protein, Braf; rat sarcoma, Ras; transforming growth factor-β, TGF-β; mothers against decapentaplegic, Smad; wingless-related integration site, Wnt; zinc finger E-box binding homeobox, ZEB; snail family transcriptional repressor, Snail; inhibitor of kappa light polypeptide gene enhancer in β-cells, kinase beta, IKKβ; programmed death-ligand 1, PD-L1; AXL receptor tyrosine kinase, AXL.

Figure 4

The mechanisms of Apigenin-mediated programmed death-ligand 1 (PD-L1) inhibition in breast cancer cells. Interferon-gamma, IFN-γ; Interleukin 6, IL-6; Janus kinase, JAK; signal transducer and activator of transcription1, STAT1; major histocompatibility complex, MHC; T-cell receptor, TCR; programmed cell death protein 1, PD-1.

Figure 5

The mechanisms of hesperidin-mediated programmed death-ligand 1 (PD-L1) inhibition in breast cancer cells. Protein kinase B, AKT; nuclear factor-kappa B, NF-ƙB.

Figure 6

The mechanisms of resveratrol-mediated programmed death-ligand 1 (PD-L1) inhibition in breast cancer cells. Interferon-gamma, IFN-γ; IFN-γ receptor 1/2, IFNGR1/2; transforming growth factor-beta, TGF-β; Janus kinase, JAK; signal transducer and activator of transcription, STAT; phosphoinositide 3-kinase, PI3K; protein kinase B, AKT; mitogen-activated protein kinase, MAPK.

Figure 7

The mechanisms of sativan-mediated programmed death-ligand 1 (PD-L1) inhibition in breast cancer cells. Signal transducer and activator of transcription, STAT; Janus kinase, JAK; Phosphoinositide 3-kinase, PI3K; protein kinase B, AKT; mammalian target of rapamycin, mTOR; mitogen-activated protein kinase, MAPK; B-Raf Serine/Threonine-Protein, BRAF; rat sarcoma, Ras; interferon-gamma, IFN-γ; IFN-γ receptor 1/2, IFNGR1/2; Snail family transcriptional repressor, Snail; Epithelial-to-Mesenchymal Transition, EMT.