Figure 2.

Regulation of PD-L1 expression in response to DNA damage in cancer cells. As per the DNA damage response pathway, DNA damage induced by IR or chemotherapeutic regents activates ATM/ATR/Chk1 signals, followed by the STAT-IRF pathway. In this pathway, STAT1/3-IRF1 appears to play an important role in PD-L1 upregulation after DNA damage. Alternatively, PD-L1 expression is regulated by the neoantigen pathway in the context of DNA damage and repair in cancer cells. Levels of mutation burden are associated with MSI. Mutation burdens and MSI are augmented by the defect of mismatch repair, chromatin remodeling, or abnormal DNA replication. Neoantigens presented by MHC class I, which is recognized by T cell receptors, activate T cells, followed by the release of IFNγ. IFNγ stimulates the STAT-IRF pathway via the IFNγ receptor (IFNGR) and upregulates PD-L1 expression in cancer cells. Another novel pathway, the cGAS/STING pathway, may also be involved in the activation of the IFN-STAT/IRF-PD-L1 pathway. Cytosolic DNA fragments induced by DNA damage activate the cGAS/STING pathway. Activation of the cGAS/STING pathway induces IFN type I (IFNα and IFNβ), which is incorporated into cancer cells via the IFNα/β receptor (IFNAR). IFNα/β-dependent signaling also activates the STAT-IRF pathway, resulting in PD-L1 upregulation.