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
  • 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.
PMID: 30589644 DOI: 10.1172/JCI123319
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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