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. Epub 2019 Feb 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / metabolism
  • Endonucleases / deficiency*
  • Endonucleases / metabolism
  • Female
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology

Substances

  • B7-H1 Antigen
  • BRCA1 Protein
  • BRCA1 protein, human
  • CD274 protein, human
  • DNA-Binding Proteins
  • IFNG protein, human
  • Membrane Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • STING protein, human
  • Interferon-gamma
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • ERCC1 protein, human
  • Endonucleases