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1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas

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Abstract

Background

Tumor-associated macrophages (TAM)s are critical regulators of glioma progression. As yet, however, TAMs in isocitrate dehydrogenase (IDH) mutated lower-grade gliomas (LGGs) have not been thoroughly investigated. The aim of this study was to determine whether 1p/19q co-deletion status affects the TAM phenotype or its prevalence in IDH mutated LGGs.

Methods

TAMs in IDH mutated LGGs were analyzed using transcriptome data from 230 samples in the TCGA database in combination with transcriptome data from single-cell RNA sequencing of IDH-mutated LGGs. Proteins potentially involved in TAM regulation were examined by immuno-staining in primary LGG samples harboring IDH mutations. Essential signaling pathways regulating TAM phenotypes were investigated in a glioma mouse model using small molecule inhibitors.

Results

Most of the TAMs in IDH-mutated LGGs expressed the M1 activation markers CD86 and TNF, whereas a subset of individual TAMs co-expressed both M1 and M2-related markers. Bioinformatics analysis in combination with immuno-staining of IDH-mutated patient samples revealed higher amounts of TAMs expressing M2-related markers in 1p/19q non-codeletion IDH-mutated LGGs compared to 1p/19q codeletion LGGs. The levels of transforming growth factor beta 1 (TGFβ1) and macrophage colony-stimulating factor (M-CSF) were significantly higher in 1p/19q non-codeletion LGGs than in 1p/19q codeletion LGGs. M-CSF and TGFβ1 signal inhibition decreased tumor growth and modulated the TAM phenotype in a glioma mouse model.

Conclusions

Our data indicate that 1p/19q co-deletion status relates to distinct TAM infiltration in gliomas, which is likely mediated by M-CSF and TGFβ1 signaling. M-CSF and TGFβ1 signaling may play a pivotal role in regulating the TAM phenotype in glioma.

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Abbreviations

1p/19q:

Chromosome 1p and chromosome 19q

IDH:

Isocitrate dehydrogenase

LGG:

Lower-grade glioma

M-CSF:

Macrophage colony-stimulating factor

scRNA-seq:

single cell RNA-sequencing

TAM:

Tumor-associated macrophage

TGFβ1:

Transforming growth factor beta 1

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Acknowledgements

The authors would like to thank the Biobank in Tangdu Hospital of the Airforce Military Medical University (**’an, China) for providing patient material, and the Core Facility of Life Science in Shaanxi Normal University for technical support.

Availability of data and materials

The analyzed datasets generated during the study are available from the corresponding author upon reasonable request.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81702489, 81911530166, 81772661, 81402081, 81870978), the “1000 Young Scholars” Program of Shaanxi Province, the National Key R&D Program of China (Grant No. 2018YFC1313003), the Natural Science Foundation of Shaanxi Province (No. 2020JQ-429), Fundamental Research Funds for the Central University (No. GK202003050, GK202003048, GK201603110), the Innovation Training Program for University Students (No. cx2019013, s201910718084) and the Natural Science Foundation of Huaihua city (2020R3118, 2020R3116).

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Author notes

  1. Yanyu Zhang, Yuan ** of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, **’an, 710119, China

    Yanyu Zhang, Yuan **e, Qiyuan He, Qingze Cao, Langjun Cui & Lei Zhang

  2. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 582, BMC, Husargatan 3, 75123, Uppsala, Sweden

    Yanyu Zhang

  3. Department of Neurosurgery, Tian** Medical University General Hospital, Tian** Neurological Institute, Key Laboratory of Post-Neuro-injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tian** City, Tian**, 300052, China

    Liqun He

  4. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185, Uppsala, Sweden

    Liqun He & Anna Dimberg

  5. Department of Spine Surgery, Huaihua No.2 Hospital, Hunan University of Medicine, Huaihua, 418000, China

    Jiefu Tang & Lei Zhang

  6. Department of Neurosurgery, Tangdu Hospital, Air Force Medical University of PLA (the Fourth Military Medical University), 569 **nsi Road, **’an, 710038, China

    Wei Guo & Liang Wang

  7. The College of Life Sciences, Northwest University, **’an, 710069, China

    Kai Hua

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  1. Yanyu Zhang
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  2. Yuan **e
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Contributions

YZ, YX and LH designed and performed research, collected, analyzed and interpreted data and wrote the manuscript; JT and LC performed research, collected, analyzed and interpreted data and wrote the manuscript; QH and QC performed research and interpreted data; KH performed research; WG and AD interpreted data; LW and LZ designed research, analyzed and interpreted data, wrote the manuscript and supervised the study.

Corresponding authors

Correspondence to Liang Wang or Lei Zhang.

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Ethical permit of using patient samples was granted by the ethics committee of Shaanxi Normal University (EP 2017–910,221).

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This manuscript does not contain personal data in any form. All patient identifiers were removed prior to analysis.

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The authors declare no conflicts of interest.

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Zhang, Y., **e, Y., He, L. et al. 1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas. Cell Oncol. 44, 193–204 (2021). https://doi.org/10.1007/s13402-020-00561-1

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