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

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

  • J Clin Invest. 2019 Mar 1;129(3):1211-1228. doi: 10.1172/JCI123319.
Roman M Chabanon 1 2 3 4 Gareth Muirhead 3 Dragomir B Krastev 3 4 Julien Adam 2 Daphné Morel 1 2 Marlène Garrido 2 Andrew Lamb 5 Clémence Hénon 1 2 Nicolas Dorvault 2 Mathieu Rouanne 1 6 Rebecca Marlow 7 Ilirjana Bajrami 3 4 Marta Llorca Cardeñosa 3 4 8 Asha Konde 3 4 Benjamin Besse 1 9 Alan Ashworth 10 Stephen J Pettitt 3 4 Syed Haider 3 Aurélien Marabelle 6 11 Andrew Nj Tutt 3 7 Jean-Charles Soria 1 Christopher J Lord 3 4 Sophie Postel-Vinay 1 2 11
Affiliations

Affiliations

  • 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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