Skip to content

Neuroscience of gliomas + microglia / TAM — cross-cutting synthesis session

Hybrid synthesis of the Monje neural-circuit-integration thread with the Bowman / Joyce / Quail microglia and tumor-associated-macrophage (TAM) work — the convergence into a single neuro-immune framework.

  • Speaker(s): Michelle Monje (Stanford); Humsa V. Venkatesh (Harvard / BWH; dopamine + neural-circuit-glioma); Frank Winkler (Heidelberg; tumor microtube networks); Johanna A. Joyce (Lausanne), Robert L. Bowman (Yale), Daniela F. Quail (McGill; microglia / TAM reprogramming); Dolores Hambardzumyan (Emory)
  • Affiliation: Stanford / Harvard / Heidelberg / Lausanne / Yale / McGill / Emory
  • Anchor type: synthesis (cross-cutting mechanism / biology cluster)
  • Day / session: Day 2 (Tue Mar 24, 2026), Neuroscience of Gliomas + Neuro-immune / TME concurrent sessions
  • Status: post-meeting; details captured from AACR Brain 26 program notes and the public Monje / Venkatesh / Joyce / Quail / Bowman published corpus; specific 2026 unpublished data from each speaker TBD pending abstract supplement

Headline finding

The two halves of glioma neuro-biology — (a) neurons-to-glioma synaptic integration (Monje thread: AMPAR-driven proliferation, neural-activity-dependent growth) plus dopaminergic and other neurotransmitter inputs (Venkatesh) plus tumor-microtube networks (Winkler) and (b) the microglia / TAM reprogramming axis (Bowman / Joyce / Quail single-cell + spatial TAM atlases, CSF-1R-class targeting, microglial-state reprogramming) — converge on a single neuro-immune framework where neural activity, TAM state, and tumor cell state co-determine progression. The session question is whether this framework yields druggable nodes beyond gabapentinoids and CSF-1R inhibitors.

Mechanism / methodology

Methodology spans patch-clamp electrophysiology in tumor slices (neuron-glioma synapses), optogenetic / chemogenetic perturbation of cortical activity in glioma-bearing mice, intravital imaging of tumor-microtube networks, single-cell and spatial atlases of TAM states across glioma grades and treatment status, and TAM-reprogramming pharmacology (CSF-1R inhibitors, complement / TREM2-class targets). Window-of-opportunity / Phase-0 trials testing circuit-modulator agents alongside standard of care are referenced as the clinical translation layer.

Mechanism / methodology deep dive

Underlying biology. Two converging axes: (1) Neurons form bona fide AMPA-receptor-mediated glutamatergic synapses onto glioma cells (Monje, Venkatesh, Winkler 2019 Nature trio), with electrical activity also coupling glioma cells via connexin-43–containing gap junctions in tumor-microtube networks (Winkler). Activity-dependent secretion of NLGN3 and BDNF drives proliferation. Dopaminergic and serotonergic inputs (Venkatesh) extend the framework beyond glutamate. (2) Microglia and tumor-associated macrophages (the dominant immune infiltrate, 30–50% of GBM mass) occupy a spectrum of disease-associated states (Joyce, Bowman, Quail single-cell atlases) characterized by TREM2, SPP1, APOE, MARCO, and CSF1R-dependent survival programs.

Therapeutic design. Circuit-modulator side: gabapentinoids (gabapentin, perampanel — AMPAR antagonist), levetiracetam (SV2A), tested as add-on to standard of care in window-of-opportunity / Phase-0 designs. TAM side: small-molecule CSF-1R inhibitors (pexidartinib, BLZ945-class), TREM2 antibodies, complement (C1q, C5aR) blockade, and antibody-drug conjugates against TAM markers; combinations with CAR-T (TAM reprogramming as adjuvant to relieve CNS T-cell exhaustion) are an early translational layer.

Resistance / failure modes. CSF-1R monotherapy has failed in randomized GBM trials (BLZ945, pexidartinib) due to TAM-state plasticity — depletion is incomplete and surviving TAMs re-skew toward immunosuppressive phenotypes. Circuit-modulator trials are limited by single-agent effect size and seizure-confounded endpoints.

Translational gaps. Whether neural-circuit + TAM combinations are additive vs redundant, and whether either translates to a randomized PFS/OS signal, remains unresolved.

Where it fits in the corpus

  • AACR 2026: AACR Annual neuro-onc and TME sessions extend Monje, Venkatesh, Joyce, Quail talks four weeks later.
  • SITC 2026: TAM-targeting and neuro-immune IO concepts; CSF-1R-class data tends to land at SITC.
  • Related Brain 26 entries: suva-glioma-cell-states.md, parrinello-injury-programs.md, monje-gd2-cart-dipg.md.

Open questions

  • Which circuit-modulator (gabapentinoid, perampanel, levetiracetam) actually translates to a glioma-PFS signal in a randomized window-of-opportunity trial — the field is at the inflection between mechanism and clinical proof.
  • Does TAM reprogramming work synergize with CAR-T (e.g., relieving CAR-T exhaustion in the CNS TME), or are they parallel programs that compete for the same patients?