From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

Abstract

Multiple clinical studies have revealed a link between genomic instability and response to anti-PD-1/PD-L1 therapy in cancer management. A recent study has revealed an important role for the ATR/Chk1 DNA damage checkpoint in regulating PD-L1 expression, raising important clinical and translational questions for therapy selection and study design.

Fig. 1

Immune activating and suppressive effects of DNA double-strand break (DSB) signalling. DSBs created by damaging agents such as ionizing radiation activate a network of signalling pathways that balance the host immune response. If repaired using an error-prone pathway such as non-homologous end joining (NHEJ) or alternative end joining, DSBs can result in somatic mutations that act as neoantigens. DNA damage can also activate the innate immune system via the STING pathway. DSB-mediated immune activation is balanced by concomitant inhibitory signalling, including upregulation of PD-L1 expression. Sato et al. show that DNA damage signalling via the checkpoint kinases ATM, ATR, and Chk1 drive PD-L1 expression on tumour cells via STAT1/STAT3/IRF3 activation