Poly(I:C) suppresses NF1-associated optic pathway glioma growth through TLR3-dependent and TLR3-independent modulation of microglial ERK signaling

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.