DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells

Abstract

Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.

Regulation of programmed death‐ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine

“…Consistent with this notion, depletion of Ku70/80 complexes enhances DSB end resection, which has been ascribed to the failure of DSB end protection, followed by increased ATR/Chk1 activation compared with that of control cells. Consistent with the increased activation of ATR/Chk1 signaling, depletion of Ku70/80 enhances further upregulation of the expression of DNA damage‐dependent PD‐L1 . Additionally, BRCA2 depletion also induces upregulation of PD‐L1 expression after DSB formation.…”

“…In our recent study, we found that depletion of Ku70/80 or BRCA2 significantly enhances the upregulation of PD‐L1 expression after IR . Ku70/80 and DNA‐PKcs bind to most DNA break ends immediately after the induction of DSBs (Figure ) .…”

“…Several recent studies reported that DNA damage induces the expression of PD‐L1 mRNA, which results in the increase in the cell surface expression of PD‐L1 . This process depends on the activity of the ATM‐ATR/Chk1 signal transduction, suggesting that the expression of PD‐L1 is controlled by DNA damage signaling.…”

“…Recent studies have suggested that the DNA damage response is an important factor influencing the efficacy of cancer immunotherapy . DNA damage induced by IR, etoposide, camptothecin, cisplatin, mitomycin C, and alkylating agents upregulates PD‐L1 expression in cancer cells . In this section, we describe the current state of knowledge of the molecular mechanisms underlying the regulation of PD‐L1 expression in response to DSB induction and the influence of DSB repair and signaling.…”

Exploiting DNA repair defects in colorectal cancer

“…A siRNA‐mediated screen of DSB repair genes found that loss of BRCA2 enhanced expression of PD‐L1, specifically in response to DSBs induced by IR or PARPi. Furthermore, loss of genes associated with the error‐prone NHEJ pathway, such as Ku80, substantially enhanced PD‐L1 expression in response to IR (Sato et al ., ). It was observed that treatment with IR and cisplatin significantly increased expression of PD‐L1 and that this effect was abrogated when cells were also treated with pharmacological inhibitors of ATR.…”