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

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, Aislinn Keane, Nadejda M. Tsankova, David H. Gutmann, Sergio A. Lira, Amaia Lujambio, Eliver E. B. Ghosn, Alexander M. Tsankov and Dolores Hambardzumyan ()
Additional contact information
Zhihong Chen: Icahn School of Medicine at Mount Sinai
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
Katherine E. Lindblad: 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
Eliver E. B. Ghosn: Emory University School of Medicine
Alexander M. Tsankov: Icahn School of Medicine at Mount Sinai
Dolores Hambardzumyan: Icahn School of Medicine at Mount Sinai

Nature Communications, 2023, vol. 14, issue 1, 1-24

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37361-8

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