Abstract
Simple SummaryPD-L1 is an important immune checkpoint molecule that is expressed in cancer tissues at various levels and plays a major role in tumor evasion from immune system. Therefore, understanding the mechanisms by which PD-L1 expression is regulated in tumor environment is important for the design of new therapeutic strategies to overcome tumor immune escape and improve the outcome of cancer treatment. Recent studies suggest that genetic, epigenetic, and transcriptional factors as well as posttranscriptional and posttranslational processes are crucial regulators of PD-L1 expression in tumor cells. This review focuses on two newly described regulations of PD-L1 mediated by oncogenes, and redox homeostasis. In this context, a recent research work describes the important role of oncogenic K-ras, growth factor receptors (FGFR1 and EGFR) and ROS in regulating PD-L1 expression in pancreatic cancer cells and aids significant new mechanistic insights in this important area.Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed.
Highlights
The discovery of molecules that act as regulators of the immune system opened a new area in tumor therapy
Epigenetics, transcriptional, posttranscriptional, and posttranslational regulations of programmed cell death ligand 1 (PD-L1) have been extensively studied and reviewed, and we will only briefly touch on these regulatory mechanisms but will focus mostly on their most recent findings; the three newly described regulations of PD-L1 expression mediated by oncogenes, growth factors, and redox homeostasis
This study suggested that a loss of phosphatase and tensin homolog (PTEN) subsequently activated phosphoinositide 3-kinase (PI3K)/Akt signaling and PD-L1 upregulation in glioma [90]
Summary
The discovery of molecules that act as regulators of the immune system opened a new area in tumor therapy. Ipilimumab (an anti-CTLA-4 antibody) was the first approved checkpoint blockade immunotherapy by the American Food and Drug Administration (FDA) in March 2011 for the treatment of advanced melanoma. PD-1 (programmed cell death-1) is a molecule expressed on T cells that was discovered by Nobel prize winner Tasuku Honjo’s team in 1992 [2]. The interaction between PD-1 and its ligands induces inhibition of T cells and prevents autoimmunity [4,6]. Based on these findings, PD-L1 antibodies were tested as immune checkpoint blockade. Given the importance of these molecules for tumor immunity, efforts were made to establish the regulation of their expression and to find better combination therapy in order to kill resistant tumors
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