Immunotherapy Utilizing NK cells and ADCC Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition
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ABSTRACT:
PROVIDER: PRJNA498086 | ENA |
REPOSITORIES: ENA
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Project description: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: We examined if olaparib, when combined with IgG1 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-15RA 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.
2018-12-11 | GSE121682 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147959 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147952 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147951 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147958 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147957 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147956 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147955 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, H3K27acα. H3K27acα activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of H3K27acα and its IFNγ-dependent phosphorylation. We identified H3K27acα as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on H3K27acα transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of H3K27acα is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147954 | GEO
Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.
2021-05-13 | GSE147953 | GEO