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Published on: November 28, 2019
PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype
Isotta Sturniolo1,2, Csongor Váróczy1,3, Zsolt Regdon1
1Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Abstract:
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.
Insights
Poly(ADP-ribose) polymerase (PARP) enzymes, particularly PARP14, are crucial in reprogramming macrophages into tumor-associated macrophages (TAMs). Inhibiting PARP14 suppresses TAM development, offering a potential anticancer strategy to enhance immune responses.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Cancers reprogram macrophages (MΦs) into tumor-promoting tumor-associated macrophages (TAMs), resembling the anti-inflammatory M2 phenotype.
- Poly(ADP-ribose) polymerase (PARP) enzymes influence MΦ biology, but their role in TAM development is unexplored.
Purpose of the Study:
- To investigate the role of PARP enzymes, specifically PARP14, in the differentiation of macrophages towards a TAM phenotype.
- To evaluate the potential of PARP inhibitors (PARPis) as a strategy to reprogram TAMs and enhance anti-cancer immunity.
Main Methods:
- Treatment of primary murine MΦs, human THP-1 monocytic MΦs, and primary human monocyte-derived MΦs with PARPis (PJ34 and MCD113).
- Analysis of M2 marker gene expression and MΦ differentiation in PARP14 knockout (KO) mice.
- Utilizing murine and human models of TAM polarization, including co-culture spheroids with breast carcinoma cells.
Main Results:
- PARP inhibitors (PJ34, MCD113) and PARP14 KO suppressed M2 marker gene expression in MΦs.
- PARP14 deficiency limited MΦ differentiation into M2 cells.
- PARPis and PARP14 KO reduced TAM polarization in both murine and human models, with increased cancer cell apoptosis observed in treated spheroids.
- Lipocalin-2, MIF, and PAI-1 identified as potential mediators of TAM differentiation dependent on ADP-ribosylation.
Conclusions:
- PARP14 plays a significant role in TAM differentiation.
- PARP14 inhibition effectively suppresses TAM polarization and promotes cancer cell apoptosis.
- Targeting PARP14 represents a promising anticancer strategy to reprogram TAMs and bolster anti-cancer immune responses.
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