PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors
PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2083755 |
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| author | Anna D. Staniszewska Joshua Armenia Matthew King Chrysiis Michaloglou Avinash Reddy Maneesh Singh Maryann San Martin Laura Prickett Zena Wilson Theresa Proia Deanna Russell Morgan Thomas Oona Delpuech Mark J. O’Connor Elisabetta Leo Helen Angell Viia Valge-Archer |
| author_facet | Anna D. Staniszewska Joshua Armenia Matthew King Chrysiis Michaloglou Avinash Reddy Maneesh Singh Maryann San Martin Laura Prickett Zena Wilson Theresa Proia Deanna Russell Morgan Thomas Oona Delpuech Mark J. O’Connor Elisabetta Leo Helen Angell Viia Valge-Archer |
| author_sort | Anna D. Staniszewska |
| collection | DOAJ |
| description | PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model. In vitro, olaparib induced BRCAm tumor cell–specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib. |
| format | Article |
| id | doaj-art-42e14e70567c4dc0ac16e7566635a844 |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-42e14e70567c4dc0ac16e7566635a8442025-08-20T02:56:37ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2083755PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumorsAnna D. Staniszewska0Joshua Armenia1Matthew King2Chrysiis Michaloglou3Avinash Reddy4Maneesh Singh5Maryann San Martin6Laura Prickett7Zena Wilson8Theresa Proia9Deanna Russell10Morgan Thomas11Oona Delpuech12Mark J. O’Connor13Elisabetta Leo14Helen Angell15Viia Valge-Archer16Early Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Boston, MA, USAEarly Oncology, Oncology R&D, AstraZeneca, Boston, MA, USAEarly Oncology, Oncology R&D, AstraZeneca, Boston, MA, USAEarly Oncology, Oncology R&D, AstraZeneca, Boston, MA, USAEarly Oncology, Oncology R&D, AstraZeneca, Alderley Park, Macclesfield, UKEarly Oncology, Oncology R&D, AstraZeneca, Boston, MA, USAEarly Oncology, Oncology R&D, AstraZeneca, Boston, MA, USAEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKEarly Oncology, Oncology R&D, AstraZeneca, Cambridge, UKPARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model. In vitro, olaparib induced BRCAm tumor cell–specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2083755PARP inhibitorolaparibcGAS-STINGimmune checkpoint blockadeBRCA |
| spellingShingle | Anna D. Staniszewska Joshua Armenia Matthew King Chrysiis Michaloglou Avinash Reddy Maneesh Singh Maryann San Martin Laura Prickett Zena Wilson Theresa Proia Deanna Russell Morgan Thomas Oona Delpuech Mark J. O’Connor Elisabetta Leo Helen Angell Viia Valge-Archer PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors OncoImmunology PARP inhibitor olaparib cGAS-STING immune checkpoint blockade BRCA |
| title | PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors |
| title_full | PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors |
| title_fullStr | PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors |
| title_full_unstemmed | PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors |
| title_short | PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors |
| title_sort | parp inhibition is a modulator of anti tumor immune response in brca deficient tumors |
| topic | PARP inhibitor olaparib cGAS-STING immune checkpoint blockade BRCA |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2083755 |
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