Glioma-neuronal circuit remodeling induces regional immunosuppression

Takahide Nejo(University of California, San Francisco), Saritha Krishna(University of California, San Francisco), Akane Yamamichi(University of California, San Francisco), Senthilnath Lakshmanachetty(University of California, San Francisco), Christian Jimenez(University of California, San Francisco), Kevin Y. Lee(University of California, San Francisco), Donovan L Baker(University of California, San Francisco), Jacob S. Young(University of California, San Francisco), Tiffany Chen(University of California, San Francisco), Su Su Sabai Phyu(University of California, San Francisco), Lan Phung(University of California, San Francisco), Marco Gallus(University of California, San Francisco), Gabriella C. Maldonado(University of California, San Francisco), Kaori Okada(University of California, San Francisco), Hirokazu Ogino(University of California, San Francisco), Payal Watchmaker(University of California, San Francisco), David Diebold(University of California, San Francisco), Abrar Choudhury(University of California, San Francisco), Andy Daniel(University of California, San Francisco), Cathryn R. Cadwell(University of California, San Francisco), David R. Raleigh(University of California, San Francisco), Shawn L. Hervey‐Jumper(University of California, San Francisco), Hideho Okada(University of California, San Francisco)
Nature Communications
May 22, 2025
10.1038/s41467-025-60074-z
Cited by 21Open Access
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Abstract

Neuronal activity-driven mechanisms influence glioblastoma cell proliferation and invasion, while glioblastoma remodels neuronal circuits. Although a subpopulation of malignant cells enhances neuronal connectivity, their impact on the immune system remains unclear. Here, we show that glioblastoma regions with enhanced neuronal connectivity exhibit regional immunosuppression, characterized by distinct immune cell compositions and the enrichment of anti-inflammatory tumor-associated macrophages (TAMs). In preclinical models, knockout of Thrombospondin-1 (TSP1/Thbs1) in glioblastoma cells suppresses synaptogenesis and glutamatergic neuronal hyperexcitability. Furthermore, TSP1 knockout restores antigen presentation-related genes, promotes the infiltration of pro-inflammatory TAMs and CD8 + T-cells in the tumor, and alleviates TAM-mediated T-cell suppression. Pharmacological inhibition of glutamatergic signaling also shifts TAMs toward a less immunosuppressive state, prolongs survival in mice, and shows the potential to enhance the efficacy of immune cell-based therapy. These findings confirm that glioma-neuronal circuit remodeling is strongly linked with regional immunosuppression and suggest that targeting glioma-neuron-immune crosstalk could provide avenues for immunotherapy.

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