Open Access

Frontiers in Immunology

, volume 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}

Hide authors affiliations Show authors affiliations: 6 affiliations

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 |

Publication type: Journal Article

Publication date: 2023-09-21

Frontiers Media S.A.

Frontiers in Immunology

scimago Q1

wos Q1

SJR: 1.941

CiteScore: 10.8

Impact factor: 5.9

ISSN: 16643224

DOI: 10.3389/fimmu.2023.1209249

Copy DOI

PubMed ID: 37809073

Immunology

Immunology and Allergy

Abstract

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.

Found

1 citation

Yagolovich Anne

🥼 🤝

PhD in Biological/biomedical sciences, lecturer

31 publications, 267 citations, 4 reviews

h-index: 10

Lomonosov Moscow State University

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Research interests

Apoptosis

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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.

GOST all authors (up to 50) Copy

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.

RIS |

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RIS Copy

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 -

BibTex

Cite this

BibTex (up to 50 authors) Copy

@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}

}

Publisher

Frontiers Media S.A.

Journal

Frontiers in Immunology

scimago Q1

wos Q1

SJR

1.941

CiteScore

10.8

Impact factor

5.9

ISSN

16643224 (Electronic)