PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

Wang, Lin; Wang, Dan; Sonzogni, O.; Ke, Shizhong; Wang, Qi; Thavamani, Abhishek; Batalini, Felipe; Stopka, Sylwia A.; Regan, Michael S.; Vandal, Steven; Tian, Shengya; Pinto, Jocelin; Cyr, Andrew M.; Bret-Mounet, Vanessa C.; Baquer, Gerard; Eikesdal, Hans Petter; Yuan, Min; Asara, John M.; Heng, Yujing J.; Bai, Péter; Agar, Nathalie Y.R.; Wulf, Gerburg M.

doi:10.1016/j.celrep.2022.111462

Cited by 26 publications

(13 citation statements)

References 55 publications

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“…A key question we aimed to address was the role of PARylation and certain individual PARP enzyme family members in MΦ polarization. In line with a recent study [27], our preliminary experiments with the clinically used PARP1/2-specific, narrow-spectrum PARP inhibitor (PARPi) Olaparib indicated that PARP1 is not likely to be involved in M2 polarization. However, a relatively high concentration of another wide-spectrum PARPi, PJ34, significantly inhibited all the M2 markers studied (Figure 1A).…”

Section: Parp14 Mediated M2 Polarization In Murine Bmdmssupporting

confidence: 84%

PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype

Sturniolo,

Váróczy,

Regdon

et al. 2024

IJMS

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Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs.

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Section: Parp14 Mediated M2 Polarization In Murine Bmdmssupporting

confidence: 84%

PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype

Sturniolo,

Váróczy,

Regdon

et al. 2024

IJMS

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“…PARPis can inhibit the activity of PARP1, PARP2, and PARP3, a group of proteins closely involved in the repair of single-strand DNA breaks. Lately, it has been suggested that PARPis have effects on macrophages and inflammatory makers [ 28 , 29 ]. Several molecules have been developed for inhibition of the PARP function, but to date, five PARP1/2 inhibitors have received marketing authorization for cancer treatment worldwide.…”

Section: Clinical Differences Of S Brca and G ...mentioning

confidence: 99%

Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors

Szentmartoni,

Mühl,

Csanda

et al. 2024

Biomedicines

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Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.

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“…Recent clinical trials are testing olaparib in combination with immune-checkpoint inhibitors 49,51,52 . Furthermore, growing studies reported that pharmacological inhibition of PARP induces activation of NK cells and reprogramming of macrophages in the tumor 53,54 . This brought us to test olaparib in combination with immune-based therapies.…”

Section: Introductionmentioning

confidence: 99%

Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition

Mukherjee,

Elia,

Garda

et al. 2024

Preprint

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Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability, promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumorigenic effect of these neutrophils and synergize with combined immunotherapeutic approaches.

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PARP-inhibition reprograms macrophages toward an anti-tumor phenotype

Cited by 26 publications

References 55 publications

PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype

PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype

Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors

Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP-inhibition

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