Cited by 68Immune Cell Function and InteractionPARP inhibition in cancer therapyCancer Immunotherapy and Biomarkers

Immunotherapy utilizing the combination of natural killer- and antibody dependent cellular cytotoxicity (ADCC)-mediating agents with poly (ADP-ribose) polymerase (PARP) inhibition

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Fenerty, Kathleen E., Padget, Michelle, Wolfson, Benjamin, Gameiro, Sofia R., Su, Zhen, Lee, John H., Rabizadeh, Shahrooz, Soon-Shiong, Patrick +1 more·2018·Journal for ImmunoTherapy of Cancer

Abstract

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. METHODS: antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. RESULTS: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15Rα further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2; and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. CONCLUSIONS: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.

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  • Pharmacological inhibition of PARP1 by veliparib or olaparib produces immunostimulatory effects by causing CGAS-independent upregulation of NKALs and death receptors on malignant cells, increasing their sensitivity to NK cell cytotoxicity.

    “pharmacological inhibition of PARP1 by veliparib or olaparib reportedly mediates immunostimulatory effects by favoring the CGAS-independent upregulation of NKALs and death receptors on the surface of malignant cells, ultimately increasing their sensitivity to NKcell cytotoxicity (Fenerty et al., 2018; Paczulla et al., 2019)”

    From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Fenerty et al., 2018

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Authors
Fenerty, K. E., Padget, M., Wolfson, B., Gameiro, S. R., Su, Z., Lee, J. H., Rabizadeh, S., Soon-Shiong, P., & Hodge, J. W.
Affiliations
  • National Institutes of Health (US)
  • EMD Serono, Inc. (United States) (US)
  • NantOmics LLC (United States) (US)
Corresponding author
Hodge, James W.
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2018-11-29
Volume
6
Issue
1
Pages
133-133
ISSN
2051-1426 (ISSN-L)
OpenAlex
W2903079493
Cited by
68
References
35
Citations by year
2026: 3 · 2025: 6 · 2024: 2 · 2023: 10 · 2022: 9 · 2021: 24 · 2020: 10 · 2019: 4
FWCI
4.08
Type
journal article
Language
en
Open access
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Cancer Institute (ZIA BC 010661)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
olaparib, PARP inhibition, natural killer cells, antibody-dependent cellular cytotoxicity, cetuximab, avelumab, prostate cancer, BRCA mutations, DR5, combination immunotherapy, DNA repair, non-small cell lung cancer, chordoma, breast cancer

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