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J Clin Invest. 2019 Mar 1;129(3):1211-1228. doi: 10.1172/JCI123319. Epub 2019 Feb 11.

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.

Author information

1
Université Paris Saclay, Université Paris-Sud, Faculté de médicine, Le Kremlin Bicêtre, Paris, France.
2
ATIP-Avenir group, Inserm U981, Gustave Roussy, Villejuif, France.
3
The Breast Cancer Now Toby Robins Breast Cancer Research Centre and.
4
CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom.
5
Sage Bionetworks, Seattle, Washington, USA.
6
Inserm U1015, Gustave Roussy, Villejuif, France.
7
The Breast Cancer Now Research Unit, King's College London, London, United Kingdom.
8
Biomedical Research Institute INCLIVA, Hospital Clinico Universitario Valencia, University of Valencia, Valencia, Spain.
9
Department of Medical Oncology, Gustave Roussy, Villejuif, France.
10
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
11
Département d'Innovations Thérapeutiques et Essais Précoces (DITEP), Gustave Roussy, Villejuif, France.

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.

KEYWORDS:

Cellular immune response; DNA repair; Lung cancer; Oncology

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