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Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma

Author

Listed:
  • Zhihong Chen

    (Icahn School of Medicine at Mount Sinai
    Emory University School of Medicine
    Emory University School of Medicine)

  • Nishant Soni

    (Icahn School of Medicine at Mount Sinai)

  • Gonzalo Pinero

    (Icahn School of Medicine at Mount Sinai)

  • Bruno Giotti

    (Icahn School of Medicine at Mount Sinai)

  • Devon J. Eddins

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Katherine E. Lindblad

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai)

  • James L. Ross

    (Emory University Department of Microbiology and Immunology, Emory Vaccine Center)

  • Montserrat Puigdelloses Vallcorba

    (Icahn School of Medicine at Mount Sinai)

  • Tanvi Joshi

    (Icahn School of Medicine at Mount Sinai)

  • Angelo Angione

    (Icahn School of Medicine at Mount Sinai)

  • Wes Thomason

    (Icahn School of Medicine at Mount Sinai)

  • Aislinn Keane

    (Icahn School of Medicine at Mount Sinai)

  • Nadejda M. Tsankova

    (Icahn School of Medicine at Mount Sinai)

  • David H. Gutmann

    (Washington University School of Medicine)

  • Sergio A. Lira

    (Icahn School of Medicine at Mount Sinai)

  • Amaia Lujambio

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai)

  • Eliver E. B. Ghosn

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Alexander M. Tsankov

    (Icahn School of Medicine at Mount Sinai)

  • Dolores Hambardzumyan

    (Icahn School of Medicine at Mount Sinai
    Emory University School of Medicine
    Emory University School of Medicine
    Icahn School of Medicine at Mount Sinai)

Abstract

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no effect on Nf1-silenced GBM model. Single-cell RNA sequencing reveals that intratumoral neutrophils promote proneural-to-mesenchymal transition and increase hypoxia in PDGFB-driven GBM. We further demonstrate neutrophil-derived TNF-a directly drives mesenchymal transition in PDGFB-driven primary GBM cells. Genetic or pharmacological inhibiting neutrophils in HCC or monocyte-deficient PDGFB-driven and Nf1-silenced GBM models extend the survival of tumor-bearing mice. Our findings demonstrate tumor-type and genotype dependent infiltration and function of monocytes and neutrophils and highlight the importance of targeting them simultaneously for cancer treatments.

Suggested Citation

  • Zhihong Chen & Nishant Soni & Gonzalo Pinero & Bruno Giotti & Devon J. Eddins & Katherine E. Lindblad & James L. Ross & Montserrat Puigdelloses Vallcorba & Tanvi Joshi & Angelo Angione & Wes Thomason , 2023. "Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37361-8
    DOI: 10.1038/s41467-023-37361-8
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    References listed on IDEAS

    as
    1. Victor Maximov & Zhihong Chen & Yun Wei & M. Hope Robinson & Cameron J. Herting & Nithya S. Shanmugam & Vasilisa A. Rudneva & Kelly C. Goldsmith & Tobey J. MacDonald & Paul A. Northcott & Dolores Hamb, 2019. "Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Patricia P. Yee & Yiju Wei & Soo-Yeon Kim & Tong Lu & Stephen Y. Chih & Cynthia Lawson & Miaolu Tang & Zhijun Liu & Benjamin Anderson & Krishnamoorthy Thamburaj & Megan M. Young & Dawit G. Aregawi & M, 2020. "Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression," Nature Communications, Nature, vol. 11(1), pages 1-22, December.
    3. Gael Boivin & Julien Faget & Pierre-Benoit Ancey & Aspasia Gkasti & Julie Mussard & Camilla Engblom & Christina Pfirschke & Caroline Contat & Justine Pascual & Jessica Vazquez & Nathalie Bendriss-Verm, 2020. "Durable and controlled depletion of neutrophils in mice," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
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