Abstract
Although the role of PD-L1 in suppressing the anti-tumor immune response is extensively documented, recent discoveries indicate a distinct tumor-intrinsic role for PD-L1 in modulating epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC)-like phenotype, metastasis and resistance to therapy. In this review, we will focus on the newly discovered functions of PD-L1 in the regulation of cancer development, describe underlying molecular mechanisms responsible for PD-L1 upregulation and discuss current insights into novel components of PD-L1 signaling. Furthermore, we summarize our current understanding of the link between PD-L1 signaling and the EMT program as well as the CSC state. Tumor cell-intrinsic PD-L1 clearly contributes to cancer stemness, EMT, tumor invasion and chemoresistance in multiple tumor types. Conversely, activation of OCT4 signaling and upregulation of EMT inducer ZEB1 induce PD-L1 expression in cancer cells, thereby suggesting a possible immune evasion mechanism employed by cancer stem cells during metastasis. Our meta-analysis demonstrated that PD-L1 is co-amplified along with MYC, SOX2, N-cadherin and SNAI1 in the TCGA endometrial and ovarian cancer datasets. Further identification of immune-independent PD-L1 functions and characterization of crucial signaling events upstream or downstream of PD-L1 in diverse cancer types and specific cancer subtypes, would provide additional targets and new therapeutic approaches.
Highlights
In cancer, the epithelial-to-mesenchymal transition (EMT) is a phenotypic process that promotes the acquisition of a mesenchymal features of epithelial tumor cells, reduces cell polarity and cell-cell adhesion, and enables them to migrate and invade more efficiently, by switching off the expression of epithelial markers, such as E-cadherin, and turning on mesenchymal markers, including N-cadherin and Vimentin [1, 2]
Cancer stem cells (CSCs) represent a fraction of undifferentiated cancer cells that are the seeds of tumor recurrence, have the ability to self-renew and exhibit significant resistance to conventional
Tumors cells that exhibit the CSC phenotype express genes associated with the EMT features and show enhanced metastatic ability, representing a novel mechanism contributing to cancer metastasis [8]
Summary
The epithelial-to-mesenchymal transition (EMT) is a phenotypic process that promotes the acquisition of a mesenchymal features of epithelial tumor cells, reduces cell polarity and cell-cell adhesion, and enables them to migrate and invade more efficiently, by switching off the expression of epithelial markers, such as E-cadherin, and turning on mesenchymal markers, including N-cadherin and Vimentin [1, 2]. Tumors cells that exhibit the CSC phenotype express genes associated with the EMT features and show enhanced metastatic ability, representing a novel mechanism contributing to cancer metastasis [8]. Tumors effectively escape immune recognition, they actively inhibit T-cell-mediated normal anti-tumor activity to promote further tumor growth and metastasis by modulating immune checkpoints, which mediate immune tolerance and inhibit the anti-tumor immune response [11] Multiple checkpoint molecules, such as PD-1/PD-L1, CTLA4, BTLA, B7H3, B7H4, HHLA2, IDO1, Tim-3, CD28, CD40, CD47, CD70, CD137, VISTA, LAG-3, and TIGIT, have been reported [11]. Disruption of the 3’ region of the PD-L1 increases mRNA stability, leading to a marked elevation of aberrant PD-L1 transcripts in multiple cancers [44]
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