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Interaction of glioma-associated microglia/macrophages and anti-PD1 immunotherapy

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Abstract

Anti-PD-1-based therapy has resulted in a minimal clinical response in malignant gliomas. Gliomas contain numerous glioma-associated microglia/macrophages (GAMs), reported to contribute to an immunosuppressive microenvironment and promote glioma progression. However, whether and how GAMs affect anti-PD-1 immunotherapy in glioma remains unclear. Here, we demonstrated that M1-like GAMs contribute to the anti-PD-1 therapeutic response, while the accumulation of M2-like GAMs is associated with therapeutic resistance. Furthermore, we found that PD-L1 ablation reverses GAMs M2-like phenotype and is beneficial to anti-PD-1 therapy. We also demonstrated that tumor-induced impairment of the antigen-presenting function of GAMs could limit the antitumor immunity of CD4+ T cells in anti-PD-1 therapy. Our study highlights the impact of GAMs activation on anti-PD-1 treatment and provides new insights into the role of GAMs in regulating anti-PD-1 therapy in gliomas.

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Data availability

All data generated or analyzed in this study are included in this published article. Further details are available upon request.

Abbreviations

APCs:

Antigen-presenting cells

Arg1:

Arginase 1

DAPI:

4′, 6-Diamidino-2-phenylindole

DMEM:

Dulbecco’s modified Eagle’s medium

FACS:

Fluorescence-activated cell sorting

GAMs:

Glioma-associated microglia/macrophages

GBM:

Glioblastoma

IFN-γ :

Interferon-γ

iNOS:

Inducible nitric oxide synthase

MCP-1:

Monocyte chemoattractant protein-1

MHC-II:

Major histocompatibility complex class II

OVA:

Ovalbumin

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-ligand 1

TME:

Tumor microenvironment

TGF-β :

Transforming growth factor-beta

TNF-α :

Tumor necrosis factor α

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Acknowledgements

We thank Cailing Yan at the Public Technology Service Center of Fujian Medical University for technical assistance with the bioluminescence imaging. This work was supported by the Natural Science Foundation of Fujian Province (No. 2019J01464) and the Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2018Y9053).

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Author notes

  1. Chunhua Wang and Quan Chen have contributed equally.

Authors and Affiliations

  1. Institute of Immunotherapy, Fujian Medical University, No. 1, Xuefu North Road, Minhou County, Fuzhou, 350122, Fujian, People’s Republic of China

    Chunhua Wang, Quan Chen, Meiqing Chen, Sizhen Guo, Ping Hou, Yulian Zou, Jun Wang, Bailin He, Qiuyu Zhang, Lieping Chen & Liqun Luo

  2. Department of Pharmacology, School of Pharmacy, Fujian Medical University, No. 1, Xuefu North Road, Minhou County, Fuzhou, 350122, Fujian, People’s Republic of China

    Chunhua Wang & Meiqing Chen

  3. Department of Neurosurgery, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Fuzhou, 350001, Fujian, People’s Republic of China

    Chunhua Wang & Quan Chen

  4. Department of Immunobiology, Yale University West Campus, MIC331, 600 West Campus Drive, West Haven, CT, 06516, USA

    Lieping Chen

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Contributions

CW and LL conceived and designed the experiments. CW and QC performed the experiments and collected and analyzed the data. MC cooperated with the establishment of tumor models. SG prepared the experimental materials and bred and identified gene knockout mice. PH and YZ isolated and purified the blocking antibodies. JW and BH provided technical guidance. CW wrote the first draft of the manuscript, and LL, QZ, and LC supervised the study and commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Liqun Luo.

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The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving animals were approved by the Fujian Medical University Institutional Animal Care and Use Committee (IACUC, No. 2019-0114) in accordance with ethical standards. All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Wang, C., Chen, Q., Chen, M. et al. Interaction of glioma-associated microglia/macrophages and anti-PD1 immunotherapy. Cancer Immunol Immunother 72, 1685–1698 (2023). https://doi.org/10.1007/s00262-022-03358-3

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