Abstract
Immunomodulatory therapies have emerged as promising treatments for cancer, where poly(I:C), a synthetic double-stranded RNA, is currently under clinical investigation for its ability to control myeloid cell function and T cell infiltration. While poly(I:C) mimics viral infection and activates Toll-like receptor 3 (TLR3), its exact mechanism of action in cancer is unknown. Our survey of multiple human tumors demonstrated that TLR3 is enriched in gliomas, particularly low-grade gliomas (LGGs; pilocytic astrocytoma, PA) in individuals with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Using two independently generated murine models of NF1-LGG (optic pathway glioma, OPG), we evaluated the efficacy of poly(I:C) and examined tumor-associated myeloid cell (TAM) function, chemokine expression, and signaling pathway activation in vivo and in vitro. We found that poly(I:C) durably suppressed tumor growth in these two Nf1-OPG strains, with sustained glioma suppression and normalized retinal nerve fiber thickness 16 weeks following treatment cessation in vivo. Importantly, poly(I:C) induced TAM Ccl3 production through both TLR3 and MDA5-dependent pathways to control Ccl3-mediated intratumoral CD8+ T cell trafficking. Since we found that Ccl3 is enriched in microglia from both human PA and mouse Nf1-OPG TAM, we used fresh murine Nf1+/− microglia to demonstrate that these independent pathways activated distinct intracellular cascades in vitro, including TLR3/MEK and MDA5/NFκB signaling, which both converge on ERK activation. Collectively, these findings identify the innate immune mechanisms by which poly(I:C) regulates TAM-mediated T cell infiltration and LGG growth, highlighting the critical role of innate immune sensors in regulating non-neoplastic cells within the brain tumor microenvironment.
Significance statement
The immunomodulatory therapy, poly(I:C), suppresses brain tumor growth by reducing tumor-associated monocyte T cell chemoattraction through two distinct pathways that converge on MEK/ERK signaling.
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Abbreviations
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- Blbp:
-
Fatty acid binding protein 7
- CNS:
-
Central nervous system
- DMG:
-
Diffuse midline glioma
- LGGs:
-
Low-grade gliomas
- MDA5:
-
Melanoma differentiation-associated-5
- NF1:
-
Neurofibromatosis type 1
- Nf1-OPG:
-
Nf1flox/mut; hGFAP-Cre
- NFκB-IN:
-
NFκB inhibitor
- OPG:
-
Optic pathway glioma
- Olig2:
-
Oligodendrocyte transcription factor 2
- PAMP:
-
Pathogen-associated molecular pattern
- PA:
-
Pilocytic astrocytoma
- RGC:
-
Retinal ganglion cell
- RNFL:
-
Retinal nerve fiber layer
- TAM:
-
Tumor-associated monocytes
- TLR3:
-
Toll-like receptor 3
Acknowledgements
We thank the Genome Technology Access Center (RRID: SCR_001030) at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. This research utilized services provided by the Washington University Histology Innovation and Service Center (WHISC). This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. This manuscript is the result of funding in whole or in part by the National Institutes of Health (NIH). It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH. Figures 1A, 2B, 5J, and 6M were created with BioRender.com (RRID: SCR_018361) under a registered license to D.H.G.
Funding
This work was partially funded by a grant from the National Institute of Neurological Disorders and Stroke (R35NS142919 to D.H.G.). S.Y. was supported financially by the fellowship of Astellas Foundation for Research on Metabolic Disorders and Daiichi Sankyo Foundation of Life Science. The Washington University Ophthalmology Core facility is supported by funding from the National Eye Institute (P30EY002687).
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Chatterjee, J., Subasic, E., Ouyang, M. et al. Poly(I:C) suppresses NF1-associated optic pathway glioma growth through TLR3-dependent and TLR3-independent modulation of microglial ERK signaling. acta neuropathol commun (2026). https://doi.org/10.1186/s40478-026-02460-2
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DOI: https://doi.org/10.1186/s40478-026-02460-2