Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells

Alvarado-Cruz, Isabel; Mahmoud, Mariam M.; Khan, Mohammed Yunus; Zhao, Shilin; Oeck, Sebastian; Meas, Rithy; Clairmont, Kaylyn; Quintana, Victoria; Zhu, Ying; Porciuncula, Angelo; Wyatt, Hailey; Ma, Shuangge; Shyr, Yu; Kong, Yong; LoRusso, Patricia; Laverty, Daniel J.; Nagel, Zachary D.; Schalper, Kurt A.; Krauthammer, Michael; Sweasy, Joann B.

doi:10.1016/j.bcp.2020.114359

Cited by 9 publications

(3 citation statements)

References 51 publications

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“…Moreover, it is now recognized that PARPi, which are known to achieve their greatest e cacy in BRCA mutated and HRD cancer cells, can also get a response in HR pro cient cancer [39]. This can be explained by both a cytotoxic activity (depending on HR de ciency), and an antitumor immune activity, that might be more relevant on HR pro cient cells [40][41][42][43][44]. This hypothesis should be further investigated in the HR pro cient population, to provide NLR as a marker able to identify those patients who can rely on their reactive antitumor-immune response to bene t from PARPi.…”

Section: Discussionmentioning

confidence: 99%

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Marchetti¹,

D’Indinosante²,

Bottoni³

et al. 2021

Preprint

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Laboratory-markers of the systemic inflammatory-response, such as neutrophil/lymphocyte-ratio (NLR) have been studied as prognostic factors in several tumors but in OC-patients their role is still controversial and no data about the possible correlation with the BRCA-status has been ever reported.We consecutively enrolled a series of 397 newly diagnosed high-grade serous-advanced OC-patients. All patients were tested for BRCA-mutational-status and blood-parameters have been collected 48 hours before staging-surgery. A significant correlation of NLR with disease distribution (p<0.005) was found and patients with NLR<4 underwent primary-debulking-surgery more frequently (p-value 0.001), with a lower surgical-complexity-score (p-value 0.002). Regarding survival-data, patients with NLR< 4 had a significant 7-month increase in mPFS (26 vs 19 months, p=0.009); focusing on the BRCA-status, among both BRCA-mutated and BRCA-wild type patients, those with lower NLR had a significantly prolonged mPFS compared to patients with NLR> 4 (BRCA-mutated: 35 vs 23 months, p= 0.03; BRCA-wt: 19 vs 16 months, p=0.05). At multivariate-analysis, independent factors of prolonged PFS were BRCA mutational status, having received complete cytoreduction and NLR< 4. Also, the strongest predictors of longer OS were BRCA-mutational status, having received complete, NLR< 4 and age.NLR is confirmed to be a prognostic marker in OC-patients and it seems unrelated with BRCA-mutational status.

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Section: Discussionmentioning

confidence: 99%

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Marchetti¹,

D’Indinosante²,

Bottoni³

et al. 2021

Preprint

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“…One study showed that PARPi induced upregulation of inflammatory factors in BRCA mutants through the cGAS/STING pathway, and in the wild type, it may induce mutations in related genes to express MHC class 1 neoantigen with strong affinity, which is consistent with the above two mechanisms. It was also suggested that PARPi treatment could induce the above two types of breast cancer response to immunotherapy [ 148 ]. Recent studies have shown that the immunomodulatory effect of PARPi can help to enhance the therapeutic effect.…”

Section: Nad Pathway-related Tumor Therapymentioning

confidence: 99%

Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment

Liu

Mohseni

et al. 2022

Cancer Cell Int

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Nicotinamide adenine dinucleotide (NAD) is the core of cellular energy metabolism. NAMPT, Sirtuins, PARP, CD38, and other molecules in this classic metabolic pathway affect many key cellular functions and are closely related to the occurrence and development of many diseases. In recent years, several studies have found that these molecules can regulate cell energy metabolism, promote the release of related cytokines, induce the expression of neoantigens, change the tumor immune microenvironment (TIME), and then play an anticancer role. Drugs targeting these molecules are under development or approved for clinical use. Although there are some side effects and drug resistance, the discovery of novel drugs, the development of combination therapies, and the application of new technologies provide solutions to these challenges and improve efficacy. This review presents the mechanisms of action of NAD pathway-related molecules in tumor immunity, advances in drug research, combination therapies, and some new technology-related therapies.

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“…The cGAS DNA sensor and the mediator STING are a branch of the innate immunity pathway that responds to foreign DNA in the cytoplasm by inducing pro-inflammatory cytokines and type I interferons ( Hopfner and Hornung, 2020 ). The cGAS/STING cascade is also triggered by the fragments of cells’ own genomic DNA in the cytoplasm ( Chen et al, 2016 ) generated during DNA damage and repair ( de Oliveira Mann and Kranzusch, 2017 ; Harding et al, 2017 ; Alvarado-Cruz et al, 2021 ; Guan et al, 2021 ), or as a consequence of telomere metabolism ( Chen et al, 2017 ; Nassour et al, 2019 ), cellular aging ( Glück et al, 2017 ; Takahashi et al, 2018 ; Lan et al, 2019 ), and other processes. The cGAS/STING pathway activation contributes to sensitization of cancer cells to radio- and chemotherapy ( Parkes et al, 2017 ; Li and Chen, 2018 ; Chen et al, 2020 ) also reviewed in ( Hayman and Glazer, 2021 ), and to their proliferative capacity ( Ranoa et al, 2018 ); furthermore, STING or cGAS are often mutated or silenced in cancer cells ( Sun et al, 2013 ; Xia et al, 2016 ; Deschamps and Kalamvoki, 2017 ; Song et al, 2017 ; de Queiroz et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells

Lazarchuk

Nguyen

Brunon

et al. 2023

Front. Mol. Biosci.

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Background: The cGAS/STING pathway, part of the innate immune response to foreign DNA, can be activated by cell’s own DNA arising from the processing of the genome, including the degradation of nascent DNA at arrested replication forks, which can be upregulated in cancer cells. Recent evidence raises a possibility that the cGAS/STING pathway may also modulate the very processes that trigger it, e.g., DNA damage repair or processing of stalled forks.Methods: We manipulated STING levels in human cells by depleting or re-expressing it, and assessed the effects of STING on replication using microfluidics-assisted replication track analysis, or maRTA, a DNA fiber assay, as well as immuno-precipitation of nascent DNA, or iPOND. We also assessed STING subcellular distribution and its ability to activate.Results: Depletion of STING suppressed and its re-expression in STING-deficient cancer cells upregulated the degradation of nascent DNA at arrested replication forks. Replication fork arrest was accompanied by the STING pathway activation, and a STING mutant that does not activate the pathway failed to upregulate nascent DNA degradation. cGAS was required for STING’s effect on degradation, but this requirement could be bypassed by treating cells with a STING agonist. Cells expressing inactive STING had a reduced level of RPA on parental and nascent DNA of arrested forks and a reduced CHK1 activation compared to cells with the wild type STING. STING also affected unperturbed fork progression in a subset of cell lines. STING fractionated to the nuclear fractions enriched for structural components of chromatin and nuclear envelope, and furthermore, it associated with the chromatin of arrested replication forks as well as post-replicative chromatin.Conclusion: Our data highlight STING as a determinant of stalled replication fork integrity, thus revealing a novel connection between the replication stress and innate immune responses.

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Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells

Cited by 9 publications

References 51 publications

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment

Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells

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Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells

Cited by 9 publications

References 51 publications

Nlr &amp; Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Nlr &amp; Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment

Innate immunity mediator STING modulates nascent DNA metabolism at stalled forks in human cells

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Product

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Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study

Nlr & Brca Mutational Status In Patients With High Grade Serous Advanced Ovarian Cancer: A Large Population Study