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PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancerChabanon, Roman M; Muirhead, Gareth; Krastev, Dragomir B; Adam, Julien; Morel, Daphné; Garrido, Marlène; Lamb, Andrew; Hénon, Clémence; Dorvault, Nicolas; Rouanne, Mathieu; Marlow, Rebecca; Bajrami, Ilirjana; Cardeñosa, Marta Llorca; Konde, Asha; Besse, Benjamin; Ashworth, Alan; Pettitt, Stephen J; Haider, Syed; Marabelle, Aurélien; Tutt, Andrew Nj; Soria, Jean-Charles; Lord, Christopher J; Postel-Vinay, Sophie
The Journal of clinical investigation, 03/2019, Volume: 129, Issue: 3Journal Article
The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.
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