PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.
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Authors
Chabanon, RM
Muirhead, G
Krastev, DB
Adam, J
Morel, D
Garrido, M
Lamb, A
Hénon, C
Dorvault, N
Rouanne, M
Marlow, R
Bajrami, I
Cardeñosa, ML
Konde, A
Besse, B
Ashworth, A
Pettitt, SJ
Haider, S
Marabelle, A
Tutt, AN
Soria, J-C
Lord, CJ
Postel-Vinay, S
Muirhead, G
Krastev, DB
Adam, J
Morel, D
Garrido, M
Lamb, A
Hénon, C
Dorvault, N
Rouanne, M
Marlow, R
Bajrami, I
Cardeñosa, ML
Konde, A
Besse, B
Ashworth, A
Pettitt, SJ
Haider, S
Marabelle, A
Tutt, AN
Soria, J-C
Lord, CJ
Postel-Vinay, S
Document Type
Journal Article
Date
2019-03-01
Date Accepted
2018-12-18
Abstract
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.
Citation
The Journal of clinical investigation, 2019, 129 (3), pp. 1211 - 1228
Source Title
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
Collections
Research Team
Gene Function