DNA-Damaging Agents Induce PD-L1 Expression through the Src-STAT1-IRF1 Pathway

Abstract

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of various cancers; however, their clinical efficacy remains limited in many patients due to resistance mechanisms. One of the mechanisms underlying this resistance is the downregulated expression of programmed cell death-ligand 1 (PD-L1) caused by mutations that impair Janus kinase 1/2 (JAK1/2) function. Therefore, finding an alternative JAK-independent pathway to enhance PD-L1 expression would be highly valuable. In the present study, we found that the chemotherapeutic agents, SN-38 and cisplatin, upregulated the transcription factor interferon regulatory factor 1 (IRF1) and its downstream target PD-L1 in the melanoma cell line A2058. This induction occurred in a JAK-independent, but signal transducer and activator of transcription 1 (STAT1)-dependent manner, with STAT1 activation mediated by the tyrosine kinase Src. Furthermore, SN-38 upregulated PD-L1 expression not only in melanoma but also across multiple cancer types. These results suggest that DNA-damaging chemotherapeutic agents upregulate PD-L1 expression through a Src-STAT1-IRF1 signaling axis, potentially improving the therapeutic efficacy of ICIs, even in tumors with defective JAK signaling.