Abstract

Background

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown anti-tumour efficacy in DNA damage response (DDR)-deficient cancers such as BRCA1-mutant triple-negative breast cancer (TNBC) and ERCC1-defective non-small cell lung cancer (NSCLC). The cGAS/STING pathway stimulates anti-cancer immunity by activating innate immune responses.

Method

We used a unique combination of isogenic models of ERCC1-deficient NSCLC and BRCA1-mutant TNBC to evaluate the effects of PARPi on tumour cell-intrinsic immune phenotypes. We performed high-content immunofluorescent screening to assess the presence of cytosolic DNA in cells exposed to several clinical PARPi, and monitored cGAS/STING pathway activation via detection of cGAS cytoplasmic re-localization, TBK1 phosphorylation, and secretion of chemotactic chemokines. Using RNA-seq, we further determined the transcriptional changes associated with loss of ERCC1 and PARPi exposure.  Using resected NSCLC series, we assessed the correlation between ERCC1 expression and levels of tumour infiltrating lymphocytes.

Results

We show that exposure to PARPi selectively triggers cGAS/STING pathway activation and type I interferon signalling in cells harbouring ERCC1 or BRCA1 defects. Mechanistically, we established that PARPi induce cell cycle-dependent formation of cytosolic chromatin fragments (CCF) in ERCC1-defective NSCLC and BRCA1-mutant TNBC cells. cGAS mediates detection of CCF, which activates cGAS/STING pathway and type I interferon response effectors, resulting in the secretion of chemotactic chemokines, such as CCL5. Importantly, these effects are suppressed in ERCC1-rescued NSCLC cells and BRCA1-revertant TNBC cells, supporting the pivotal role of DDR defects in eliciting cell-autonomous innate immune phenotypes in response to PARPi. Loss of ERCC1, per se, resulted in enhanced STING expression and type I interferon transcriptomic signature in NSCLC cells, and low ERCC1 expression correlated with increased lymphocytic infiltration in human NSCLC samples.

Conclusion

Our data unveil an unexpected immunomodulatory potential of PARPi that could be exploited therapeutically in combination with immunotherapies in appropriately selected populations; a corresponding academy-sponsored clinical trial is underway (EudraCT 2018-001744-62).