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.
Keywords: PD-L1; ROS; cancer; combination therapy; growth factors; oncogenes; redox homeostasis.