Figure 2.

A schematic overview illustrating the various aspects involved in the regulation of PD-1/PD-L1 transcription. Co-stimulation via CD28 in conjunction with the TCR initiates the activation of several signaling pathways, including the Ras/MEK/ERK, NF-κB, and PI3K/AKT cascade, which in turn leads to an upregulation of PD-1 transcription. On the other hand, the expression of PD-L1 on tumor cells is regulated via 1) oncogenic activation of different signaling pathways and by 2) the presence of inflammatory signaling molecules (i.e., interferon-γ) released by effector immune cells such as the cytotoxic T cell in the tumor microenvironment. AKT = protein kinase B; APC = antigen presenting cell; ERK = extracellular signal-regulated kinase; IFNGR = interferon-gamma receptor; IFN-γ = interferon-gamma; IRF-1 = interferon regulatory factor-1; JAK = janus tyrosine kinase; MEK = mitogen-activated protein kinase; MHC = major histocompatibility complex; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death-ligand 1; PI3K = phosphatidylinositol-3 kinase; PTEN = phosphatase and tensin homolog; STAT = signal transducer and activator of transcription; TCR = T cell receptor.