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Frontiers in Immunology

, том 14

TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content

Sinem Gunalp ^{1, 2}

Derya Goksu Helvaci ^{1, 3}

Aysenur Oner ^{1, 2}

Ahmet Bursalı ¹

Alessandra Conforte ⁴

Hüseyin Güner ^{1, 5}

Gökhan Karakülah ^{1, 2}

Eva Szegezdi ⁴

Duygu Sag ^{1, 2, 6}

Скрыть аффилиации авторов Показать аффилиации авторов: 6 аффилиаций

Izmir Biomedicine and Genome Center, Türkiye |

Department of Genomic Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Türkiye |

Faculty of Medicine, Dokuz Eylul University, Türkiye |

⁴

School of Biological and Chemical Sciences, University of Galway, Ireland |

⁵

Department of Molecular Biology and Genetics, Faculty of Life and Natural Science, Abdullah Gül University, Türkiye |

⁶

Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Türkiye |

Тип публикации: Journal Article

Дата публикации: 2023-09-21

Frontiers Media S.A.

Frontiers in Immunology

scimago Q1

wos Q1

БС1

SJR: 1.941

CiteScore: 10.8

Impact factor: 5.9

ISSN: 16643224

DOI: 10.3389/fimmu.2023.1209249

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PubMed ID: 37809073

Immunology

Immunology and Allergy

Краткое описание

Background

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known.

Methods

Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients.

Results

TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content.

Conclusions

TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization.

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Gunalp S. et al. TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content // Frontiers in Immunology. 2023. Vol. 14.

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Gunalp S., Helvaci D. G., Oner A., Bursalı A., Conforte A., Güner H., Karakülah G., Szegezdi E., Sag D. TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content // Frontiers in Immunology. 2023. Vol. 14.

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TY - JOUR

DO - 10.3389/fimmu.2023.1209249

UR - https://doi.org/10.3389/fimmu.2023.1209249

TI - TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content

T2 - Frontiers in Immunology

AU - Gunalp, Sinem

AU - Helvaci, Derya Goksu

AU - Oner, Aysenur

AU - Bursalı, Ahmet

AU - Conforte, Alessandra

AU - Güner, Hüseyin

AU - Karakülah, Gökhan

AU - Szegezdi, Eva

AU - Sag, Duygu

PY - 2023

DA - 2023/09/21

PB - Frontiers Media S.A.

VL - 14

PMID - 37809073

SN - 1664-3224

ER -

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@article{2023_Gunalp,

author = {Sinem Gunalp and Derya Goksu Helvaci and Aysenur Oner and Ahmet Bursalı and Alessandra Conforte and Hüseyin Güner and Gökhan Karakülah and Eva Szegezdi and Duygu Sag},

title = {TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content},

journal = {Frontiers in Immunology},

year = {2023},

volume = {14},

publisher = {Frontiers Media S.A.},

month = {sep},

url = {https://doi.org/10.3389/fimmu.2023.1209249},

doi = {10.3389/fimmu.2023.1209249}

}

Издатель

Frontiers Media S.A.

Журнал

Frontiers in Immunology

scimago Q1

wos Q1

БС1

SJR

1.941

CiteScore

10.8

Impact factor

5.9

ISSN

16643224 (Electronic)