Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating
Amanda de Andrade Costa1, Jit Chatterjee1, Olivia Cobb1
1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Background:
Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored.
Methods:
A combination of bulk and single-cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments.
Results:
We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8+ T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8+, but not CD4+, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment.
Conclusions:
Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation.
Insights
Targeting T cells and microglia during early brain tumor development can prevent glioma formation. Inhibiting specific molecules like Ccl2 and Ccl5 halts tumor growth in preclinical models.
Area of Science:
- Neuro-oncology
- Cancer immunology
- Tumor microenvironment
Background:
- Brain tumor progression involves interactions between cancer cells and non-cancerous cells.
- Neurofibromatosis type 1 (NF1) is linked to optic pathway gliomas (OPGs).
- Previous studies showed T cells and microglia influence established NF1-OPG growth.
Purpose of the Study:
- To investigate the role of stromal interactions in the initial formation of low-grade gliomas (LGGs).
- To identify key immune cell populations and molecular pathways involved in early gliomagenesis.
- To evaluate the potential of targeting these interactions for preventing LGG development.
Main Methods:
- Utilized murine models of NF1-associated OPGs.
- Employed bulk and single-cell RNA sequencing, immunohistochemistry, and T cell assays.
- Applied pharmacologic and antibody-mediated inhibition strategies.
Main Results:
- T cells and microglia are major non-neoplastic immune cells in murine and human LGGs.
- CD8+ T cells are recruited via increased Ccl2 receptor (Ccr4) expression, dependent on NF1/RAS.
- Temporal inhibition of microglia Ccl5 (3-6 weeks) and T cell Ccl2 (7-10 weeks) prevented tumor formation.
Conclusions:
- Stromal interactions are critical for early LGG formation.
- Targeting Ccl5 and Ccl2 during specific developmental windows can durably block murine LGG development.
- These findings offer a proof-of-concept for therapeutic strategies against early-stage gliomas.
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