The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer

SIMPLE SUMMARY: PD-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. ABSTRACT: 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.