Fig. 1

Adaptive resistance and innate resistance. (Left, adaptive resistance) Upon recognition of tumor antigens, TILs produce IFN-γ, which induces PD-L1 expression via nuclear NF-κB activation and the PKD2 signal pathway. In tumor hypoxia microenvironmental condition, HIF-1 regulates the expression of PD-L1 by binding directly to the hypoxia response element-4 in the PD-L1 proximal promoter. Upon binding to PD-1, PD-L1 delivers a suppressive signal to T cells, leading to T cell dysfunction. (Right, innate resistance) Tumor cell PD-L1 expression that might be related to oncogenic signaling pathways or oncogenic gene mutation as inherent in the tumor cell. Oncogenic signals (such as PI3K/Akt/mTOR, JAK/STAT 3, and EGFR/MAPK pathway) or oncogenic gene mutation (such as PTEN, ALK, and EGFR) upregulate PD-L1 expression on tumors as innate resistance. Abbreviations: IFN-γ interferon-γ, TILs tumor-infiltrating lymphocytes, NF-κB nuclear factor-kappaB, PI3K phosphatidylinositol 3-kinase, HIF-1 hypoxia inducible factor-1, JAK/STAT3 Janus kinase/signal transducer and activator of transcription 3, EGFR/MAPK epidermal growth factor receptor/mitogen-activated protein kinase, ALK anaplastic lymphoma kinase, PKD2 polycystin 2, PD-1 programmed death 1, PD-L1 programmed cell death-ligand 1, AKT protein kinase B, mTOR mammalian target of rapamycin, PTEN phosphatase and tensin homolog