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Mahmoud S.
Alghamri et al.
of the Department of Neurosurgery, University of Michigan, Ann Arbor School of Medicine, established a glioblastoma model to study the effect
of G-CSF secreted by IDH1-mutant glioma stem cells on immunotherapy.
The results were published online in the October 2021 issue of Science Advances
.
- Excerpted from the article chapter
【Ref: Alghamri MS, et al.
Sci Adv.
2021 Oct; 7(40):eabh3243.
doi: 10.
1126/sciadv.
abh3243.
Epub 2021 Sep 29.
】
Research background
The glioma IDH-mutant mIDH1 synthetic tumor metabolite 2HG can induce epigenetic reprogramming
of the transcriptome of glioma cells by inhibiting DNA and histone demethylase.
Studies have found that immunotherapy (TK/Flt3L) has a significant effect on mIDH1 glioma.
Blocking granulocyte colony-stimulating factor (G-CSF) in mIDH1 glioma-bearing mice can restore immunosuppression of tumor-infiltrating myeloid cells, suggesting that G-CSF can reprogram myeloid cells, and increase non-inhibitory myeloid cells in mIDH1 glioma TME to improve the efficacy
of immunotherapy.
Mahmoud S.
Alghamri et al.
of the Department of Neurosurgery, University of Michigan, Ann Arbor School of Medicine, established a glioblastoma model to study the effect
of G-CSF secreted by IDH1-mutant glioma stem cells on immunotherapy.
The results were published online in the October 2021 issue of Science Advances
.
Research methods
.
The TK/Flt3L-induced T cell response peaked
approximately 7 days after immunotherapy.
SPADE Spanning Tree Progression Analysis revealed that the glioma tumor microenvironment (TME) contains several immune cell types, such as macrophages, DCs, B cells, natural killer (NK) cells, CD8+ T cells, and CD4+ T cells
.
In the population of Lin-, the frequency of LSK (Lin-/c-Kit+/Sca-1+) in BM from mIDH1-bearing mice increased 2.
2-fold (P<0.
05).
<b26>
To compare the molecular differences of TME-derived granulocytes on a single-cell basis, the researchers used single-cell RNA sequencing (scRNA-seq) and large-scale cell counting
.
In mIDH1 tumors, 14 different cell clusters were identified, expressing markers of known major immune cell types
.
Study results
Transcriptome analysis showed that C7 from wtIDH1 TME and C1 from mIDH1 TME (PMN-MDSCs) had the highest
levels of Fcgr3 in C7 from wtIDH1 TME and C1 from mIDH1 TMEs.
In contrast, Fcgr2b has no differential expression
between any clusters.
Myeloid clusters are the most abundant immune cells
infiltrating wtIDH1 and mIDH1 human gliomas.
GM-CSF, CXCL1, CXCL10, IL-5, macrophage inflammatory protein 2, IL-6, and tumor necrosis factor-ɑ are among
the cytokines downregulated in mIDH1-conditioned media.
CSF3 is mostly expressed by major tumor cell clusters and belongs to stem-like cells
.
After G-CSF depletion in mIDH1-bearing animals with G-CSF neutralizing antibodies, G-CSF treatment significantly reduced serum G-CSF levels (P<0.
01) and granulocyte ratio (P<0.
05) in mIDH1 tumor mice<b20>.
To reveal whether G-CSF alone is sufficient to induce the expression of non-immunosuppressive neutrophils, the researchers injected wtIDH1-bearing mice with recombinant G-CSF to explore the molecular mechanism
by which mIDH1 reshapes tumor-infiltrating granulocytes into non-inhibitory granulocytes.
Conclusion of the study
The results of this study showed that immunotherapy (TK/Flt3L) was effective in mIDH1 glioma due to the reprogramming of myeloid cells infiltrated in the tumor microenvironment
.
Myeloid cell reprogramming is triggered
by G-CSF secreted by mIDH1 glioma stem cells.
G-CSF reprogrammed myeloid cells to generate non-inhibitory myeloid cells within mIDH1 glioma TME, improving the efficacy of
immunotherapy.
