G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy

Mahmoud S Alghamri^{1

2}, Brandon L McClellan^{1

2

3}, Ruthvik P Avvari^{1

2}, Rohit Thalla^{1

2}, Stephen Carney^{1

2}, Carson S Hartlage^{1

2}, Santiago Haase^{1

2}, Maria Ventosa^{1

2}, Ayman Taher^{1

2}, Neha Kamran^{1

2}, Li Zhang^{1

2}, Syed Mohd Faisal^{1

2}, Felipe J Núñez^{1

2}, María Belén Garcia-Fabiani^{1

2}, Wajd N Al-Holou¹, Daniel Orringer¹, Shawn Hervey-Jumper⁴, Jason Heth¹, Parag G Patil¹, Karen Eddy¹, Sofia D Merajver⁵, Peter J Ulintz⁵, Joshua Welch⁶, Chao Gao⁶, Jialin Liu⁶, Gabriel Núñez⁷, Dolores Hambardzumyan⁸, Pedro R Lowenstein^{1

2

9}, Maria G Castro^{1

2

9}

Affiliations

¹ Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁶ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁷ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁸ Department of Oncological Sciences, The Tisch Cancer Institute, and Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.

PMID: 34586841
PMCID: PMC8480930
DOI: 10.1126/sciadv.abh3243

G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy

Mahmoud S Alghamri et al. Sci Adv. 2021 Oct.

. 2021 Oct;7(40):eabh3243.

doi: 10.1126/sciadv.abh3243. Epub 2021 Sep 29.

Authors

Affiliations

¹ Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ Department of Neurosurgery, University of California San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁶ Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁷ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁸ Department of Oncological Sciences, The Tisch Cancer Institute, and Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.

PMID: 34586841
PMCID: PMC8480930
DOI: 10.1126/sciadv.abh3243

Abstract

Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells’ transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells’ compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma–bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.

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Figures

**Fig. 1.. *mIDH1* tumor models have enhanced response to immune-stimulatory gene therapy irrespective of myeloid cell depletion.**
(A) Schematic showing the mechanism by which TK/Flt3L gene therapy recruits and activates a tumor-specific T cell response. (B) Schematic illustrating the treatment strategy of the TK + Flt3L gene therapy in combination with Ly6G depletion in *wtIDH1* or *mIDH1* tumor–bearing mice. WT, wild type. (C and D) Kaplan-Meier survival curves of implanted mice-bearing *wtIDH1* or *mIDH1* tumors, treated with TK + Flt3L, Ly6G depletion, or combination therapy. dpi, days postimplantation; NS, not significant. (E) Tumor-specific CD8 T cell frequency within the TME of *wtIDH1* or *mIDH1* tumors treated with TK + Flt3L, Ly6G depletion, or combination therapy was analyzed by staining for SIINFEKL-Kb tetramers. (F) Hematoxylin and eosin staining of brain sections from *mIDH1* tumors treated with saline, αLy6G, TK/Flt3L, and TK/Flt3L + αLy6G. (G) Schematic illustrating the treatment strategy of the TK + Flt3L gene therapy in combination with Ly6G depletion in *mIDH1* tumor–bearing mice. Most *mIDH1* tumor–bearing mice (90%) survived long term in response to TK/Flt3L gene therapy regardless of Ly6G depletion. The long-term survived mice were rechallenged at day 90 after implantation. (H) Kaplan-Meier survival plot for rechallenged long-term survivors from *mIDH1* + TK/Flt3L + isotype (N = 4), *mIDH1* + TK/Flt3L + Ly6G dep (N = 5), or control (*mIDH1* + untreated) (N = 5). Data were analyzed using the log-rank (Mantel-Cox) test. Scale bars, 1 mm. **P < 0.01 and ***P < 0.005, One-way analysis of variance (ANOVA).

**Fig. 2.. *mIDH1* glioma models have high expansion of granulocytic myeloid cell population (CD45^high/CD11b⁺/Ly6G⁺).**
(A and B) SPADE analysis of mass cytometry (CyTOF) data represents immune cell composition within the TME of SB-induced *wtIDH1* (A) or *mIDH1* (B) tumors. Insets are viSNE visualizations of high-dimensional mass cytometry data; color intensity represents the Gr-1 expression level. (C) Phenotypic characterization of CD45^high/CD11b⁺/Gr-1⁺ population as granulocytic or monocytic based on the expression of Ly6G or Ly6C at symptomatic stage. Most of the CD45^high/CD11b⁺/Gr-1⁺ in the *mIDH1* glioma TME are CD45^high/CD11b⁺/Ly6G⁺ (granulocytic) cells. (D and E) Flow cytometry analysis of the frequency of MDSCs (CD45^high/CD11b⁺/Gr-1⁺) within the TME at the midstage of tumor implantation (D) and at the symptomatic stage (E). The percentage of CD45^high/CD11b⁺/Gr-1⁺ cells was higher in *mIDH1* tumors compared to *wtIDH1* tumors. (F and G) CyTOF analysis of CD45^high/CD11b⁺/Gr-1⁺ cells in blood from mice with no tumor (normal) and SB-induced *wtIDH1* or *mIDH1* glioma. (H) Phenotypic characterization of circulating CD45^high/CD11b⁺/Gr-1⁺ cells according to expression of Ly6C or Ly6G. (I and J) CyTOF analysis of CD45^high/CD11b⁺/Gr-1⁺ cells from the spleens of mice with no tumor and SB-induced *wtIDH1* or *mIDH1* glioma. (K) Phenotypic characterization of splenic CD45^high/CD11b⁺/Gr-1⁺ cells according to expression of Ly6C or Ly6G. (L) Schematic figure of the in vitro T cell proliferation assay. (M) Flow analysis of the inhibitory potential of CD45^high/CD11b⁺/Ly6G⁺ cells from TME of *wtIDH1* or *mIDH1* tumor. N = normal, **P < 0.01, ***P < 0.005, and ****P < 0.0001, ANOVA.

**Fig. 3.. Phenotypic and molecular characterization of myeloid cell lineages in *mIDH1* glioma.**
(A to C) Representative flow cytometry plots and quantification of the percentage of (B) LSK (Lin⁻/c-Kit⁺/Sca-1⁺) and (C) MP (Lin⁻/c-Kit⁺/Sca-1⁻) in BM from normal mice (N), and mice implanted with *wtIDH1* or *mIDH1* neurospheres. (D) Schematic diagram representing the shift in myelopoeisis within *mIDH1* tumor–bearing mice. Thick arrows represent predominant developmental pathways in *mIDH1* tumor–bearing mice. (E to H) Flow cytometry analysis of the frequency of (E and F) GMPs (Lin⁻/IL-7Rα⁻/c-Kit⁺/Sca-1⁻/CD34⁺/FcyRII/III^high) and (G and H) CLPs (c-Kit^low/Sca-1^low/Lin⁻/IL-7Rα⁺) in the BM from normal and *wtIDH1* or *mIDH1* tumor–bearing mice. (I to K) Representative flow cytometry plots and quantification of the percentage of (J) LSK and (K) MPs in spleen from normal and *wtIDH1* or *mIDH1* tumor–bearing mice. (L and M) Representative flow cytometry plot and quantitation analysis showing the frequency of common GMPs in spleens from normal mice and *wtIDH1* and *mIDH1* tumor–bearing animals. (N and O) Representative flow cytometry plot and quantitation analysis showing the frequency of CLPs in spleens from normal mice, *wtIDH1* and *mIDH1* tumor–bearing mice. (P to U) Flow cytometry analysis of immunosuppressive/costimulatory markers in the CD45^high/CD11b⁺/Ly6G⁺ population within TME of *wtIDH1* (black) or *mIDH1* (blue). (V) Heatmap showing the normalized expression of genes related to PMN-MDSC immunosuppressive signature in myeloid cells (CD11b⁺/ Gr-1⁺) from *wtIDH1* or *mIDH1* TME. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.0001, one-way ANOVA.

**Fig. 4.. Nonsuppressive neutrophils and preneutrophils are the major granulocyte population in *mIDH1* tumors.**
(A) Schematic overview of single-cell sequencing and CyTOF analysis of immune cells infiltrating *wtIDH1* and *mIDH1* tumors. (B) Combined Seurat analysis of immune cells from *mIDH1* shown in Uniform Manifold Approximation and Projection (UMAP) projection results in various distinct clusters of immune cells (N = 2). (C) Heatmap of differentially expressed immunosuppressive and neutrophil-related genes between the three granulocytic clusters in *mIDH1* TME. (D and E) Mass cytometry analysis of granulocytes from TME of (D) *wtIDH1* or (E) *mIDH1* tumors. (F) T cell proliferation analysis to assess the inhibitory potential of myeloid cells cluster (C7) from *wtIDH1* tumors and C1, C2, and C3 myeloid cell clusters isolated from *mIDH1* tumors. (G) Heatmap representing normalized expression level of myeloid biomarkers within granulocytes from the TME of normal mice, mice implanted with *wtIDH1* tumors, and C1, C2, and C3 clusters from the TME of *mIDH1* tumors. (H and I) Unsupervised clustering and viSNE visualization of granulocytes from *wtIDH1* (H) or *mIDH1* (I) tumors using the biomarker shown in (G). (J) Flow plots and quantitation analysis of the proportion of bona fide PMN-MDSCs (CD45^high/CD11b⁺/Ly6G⁺/CD16/32⁺) infiltrating normal mice and *wtIDH1* or *mIDH1* tumors. *P < 0.05, **P < 0.01, ***P < 0.005, ANOVA.

**Fig. 5.. CD16/32 is a specific marker that defines bona fide immunosuppressive PMN-MDSCs.**
(A and B) Violin plot showing the expression of the *Fcgr3* (A) or *Fcgr2b* (B) gene in each granulocytic cluster infiltrating the *wtIDH1* tumor (C7) or *mIDH1* tumors (C1, C2, and C3). *Fcgr3*, but not *Fcgr2b*, is expressed at high level in both immunosuppressive granulocytic MDSCs clusters (C7 and C1). (C) Schematic of the in vitro T cell proliferation assay to analyze immune suppressive properties of CD45^high/CD11b⁺/Ly6G⁺/CD16/32^−/+. Sorted CD45^high/CD11b⁺/Ly6G⁺/CD16/32-positive or CD45^high/CD11b⁺/Ly6G⁺/CD16/32-negative cells were cocultured with CFSE-labeled splenocytes from *Rag2/OT-1* transgenic mouse. Cultures were stimulated with 100 nM SIINFEKL peptide for 4 days, after which proliferation was analyzed by flow cytometry. (D) Representative flow plots showing CFSE staining of unstimulated splenocytes (T only), splenocytes undergoing rapid proliferation in response to SIINFEKL (T + SIIN), and the effect of SIINFEKL-induced T cell proliferation in the presence of CD45^high/CD11b⁺/Ly6G⁺/CD16/32-negative or CD45^high/CD11b⁺/Ly6G⁺/CD16/32-positive cells from the TME of *mIDH1* tumors. (E) Quantitation analysis of the inhibitory potential of CD45^high/CD11b⁺/Ly6G⁺/CD16/32-negative or CD45^high/CD11b⁺/Ly6G⁺/CD16/32-positive cells sorted from TME of *mIDH1* tumor. CD45^high/CD11b⁺/Ly6G⁺/CD16/32-positive cells inhibit T cell proliferation, whereas CD45^high/CD11b⁺/Ly6G⁺/CD16/32-negative cells did not suppress T cell proliferation. *P < 0.05, **P < 0.01, and ***P < 0.005, one-way ANOVA.

**Fig. 6.. PMN-MDSC gene signature is expressed in a higher proportion of tumor-infiltrating immune cells in human *wtIDH1* glioma.**
Seurat analysis of immune cells from (A) *wtIDH1* or (B) *mIDH1* primary tumor samples, shown in UMAP projection, results in various distinct clusters. (C and D) Heatmaps showing the differentially expressed genes in each cluster of (C) *wtIDH1* tumor and (D) *mIDH1* tumor samples. (E) Bar plots showing the relative PMN-MDSC gene signature score in each cluster of primary human samples. (F) Quantification of the tumor-infiltrating PMN-MDSCs/total immune cells calculated from scRNA-seq data. ***P < 0.001, Student’s t test.

**Fig. 7.. G-CSF is a major epigenetically regulated cytokine expressed by glioma stem-like cells.**
(A) Cytokine array analysis performed on conditioned media from *wtIDH1* and *mIDH1* neurospheres. (B) H3K4me3 and (C) H3K27me3 occupancy at specific genomic regions of *Csf3* gene. (D) Experimental design for ChIP-seq analysis of mIDH1 patient-derived neurospheres (SF10602) treated with vehicle or the *mIDH1* inhibitor (AGI-5198). (E to I) Histone marks occupancy at specific genomic regions of *CSF3* gene in SF10602 treated with *mIDH1* inhibitor (AGI-5198, blue) compared to untreated cells (gray). (J to L) Quantitative ELISA of the G-CSF level in mouse serum of tumor-bearing animals (J), conditioned media from cultured mouse neurospheres (K), and conditioned media from cultured human neurospheres (L) expressing *wtIDH1* or *mIDH1*. (M) Analysis of TCGA data for *CSF3* gene expression in *mIDH1* glioma patients harboring *TP53* and *ATRX* mutation (n = 99) and *wtIDH1* (n = 82). (N) Quantitative ELISA of serum G-CSF from glioma patients with *wtIDH1* or *mIDH1* (astrocytoma). *P < 0.05, **P < 0.01, and ***P < 0.005, Student’s t test.

**Fig. 8.. Glioma *mIDH1* stem-like cells are the major source of G-CSF expression.**
(A and B) Combined Seurat analysis shown in tSNE projection of whole tumor from *mIDH1* GEMM of glioma resulted in various distinct clusters of cells. The expression of *CSF3* was analyzed between the clusters. Stem-like cells were the major clusters that have the highest *CSF3* expression (N = 2). (C to G) Feature plots represent the expression of (C) *csf3*, (D) *tcf4*, (E) *sox9*, (F) *sox11*, and (G) *sox4*. (H to M) Flow cytometry analysis of the GCSFR expression in glioma patient-derived cells with *wtIDH1* or *mIDH1*. (N) Quantification of GCSFR expression in cultured human glioma cells with *wtIDH1* or *mIDH1*. MFI, Mean fluorescence intensity. (O and P) Flow cytometry analysis of the GCSFR expression in mouse neurospheres developed by the SB model with *wtIDH1* or *mIDH1.* (Q and R) Flow cytometry analysis of the GCSFR expression on CD11b⁺ Gr-1⁺ derived from the TME of *wtIDH1* or *mIDH1* tumor–bearing mice. (S) Quantification of GCSFR expression in conditions (O) to (R).

**Fig. 9.. G-CSF neutralization restores the immunosuppressive properties in myeloid cells and enhances the efficacy of immunotherapy.**
(A) Schematic showing experimental design of G-CSF neutralization in *wtIDH1* and *mIDH1* tumor–bearing mice. (B) Quantitative ELISA of serum G-CSF from *mIDH1* glioma-bearing mice treated with either isotype (red) or αG-CSF (blue). (C) Flow analysis of CD45^high/CD11b⁺/Ly6G⁺ cells from tumor, spleen, and BM of tumor-bearing mice treated with either isotype or αG-CSF. (D) T cell proliferation assay of CD45^high/CD11b⁺/Ly6G⁺ infiltrating *mIDH1* tumor treated with isotype or αG-CSF. (E) Kaplan-Meier survival analysis of mice implanted with either *wtIDH1* or *mIDH1* neurospheres treated with isotype or αG-CSF. (F) Kaplan-Meier survival analysis of TCGA-LGG astrocytoma *wtIDH1* or *mIDH1* patients with high and low *CSF3* expression. (G) Kaplan-Meier survival analysis of Chinese Glioma Genome Atlas (CGGA)–secondary astrocytoma *wtIDH1* or *mIDH1* patients with high and low levels of *CSF3* expression. (H to M) Kaplan-Meier survival analysis of the different types of tumors in the TCGA data according to *CSF3* expression (high or low). LGG is the sole tumor within the TCGA database in which patients who express a high level of *CSF3* have a favorable prognosis compared to patients with low *CSF3* expression. *P < 0.05, **P < 0.01, and ***P < 0.005, ANOVA.

**Fig. 10.. G-CSF induces the expansion of nonsuppressive neutrophils and enhances the efficacy of TK/Flt3L immunotherapy in *wtIDH1* glioma.**
(A) Experimental design of rG-CSF or vehicle administration in *wtIDH1* tumor–bearing animals. (B) Flow analysis of granulocytes infiltrating *wtIDH1* tumors after treatment with vehicle or rG-CSF. (C and D) Flow analysis of CD16/32 and PD-L1 expression on granulocytes isolated from *wtIDH1* tumor–bearing animals treated with vehicle (blue) or rG-CSF (red). (E) Flow analysis of the inhibitory potential of CD45^high/CD11b⁺/Ly6G⁺ cells isolated from TME of *wtIDH1* tumor–bearing mice treated with vehicle (blue) or with rG-CSF (red). (F and G) Kaplan-Meier survival analysis of mice bearing *wtIDH1* tumors (F) (NPA) or (G) (CPA) treated with either isotype (blue) or rG-CSF (red). (H) Schematic diagram illustrates the treatment strategy of the TK + Flt3L gene therapy in combination with rG-CSF in *wtIDH1* tumor–bearing mice. (I) Kaplan-Meier survival curves of mice bearing *wtIDH1* tumors, treated with TK + Flt3L, rG-CSF, or combination therapy. (J) Proposed model of aberrant granulocyte differentiation in the *mIDH1* tumor. *P < 0.05, **P < 0.01, and ****P < 0.0001, ANOVA.

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G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy

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G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy

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Abstract

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References

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