{
  "abstract": "Background Glioblastoma (GBM) is the most aggressive primary brain cancer in adults, with median overall survival less than 15 months. Previous studies have shown that glioma cells utilize neuronal synapses for promoting tumorigenesis, with increased neuronal-glioma synaptogenesis linked to poor prognosis. However, the preceding mechanism of cancer-directed axonogenesis remains unclear, particularly in the context of tumor recurrence after surgical resection. Neuropilin-2 (NRP2) is a transmembrane receptor involved in neoangiogenesis, immunosuppression, and axonal guidance that has been implicated in other neurological diseases and solid tumors. We hypothesize that upregulation of NRP2 in the tumor microenvironment (TME) may accelerate disease progression in both primary and recurrent GBM.Methods Human GBM tissue specimens were analyzed for NRP2 upregulation across immune, neuronal, glial, and tumor cell compartments via single-cell RNA sequencing and immunohistochemistry. C57BL/6 murine GBM models (CT-2A, SB28) were used to define mechanisms associated with NRP2 signaling with corresponding flow cytometry, Seahorse metabolic assays, immunofluorescence, western blotting, and in vivo angiographic and diffusion tensor imaging. Functional analysis of NRP2 blockade included neurite outgrowth, radiographic tumor progression, and survival.Results NRP2 was upregulated in myeloid-derived suppressor cells (MDSCs) in both human and murine GBM. NRP2+ MDSCs promoted neurite extension toward CT-2A and SB28 glioma cells in vitro and amplified neurotrophic signaling with increased secretion of BDNF. Inhibition of NRP2 mitigated neurite extension and axonogenesis towards tumor cells (P<0.001 ). Mechanistically, activation of NRP2 by VEGF-C and Semaphorin-3C induced IL-10 and BDNF production, enhancing axonogenesis (P<0.0001). Inhibition of NRP2 in vivo decreased immunosuppression in the TME with increased infiltration of anti-tumoral CD86+MHCII+ myeloid cells and associated increase in CD8+ T cell IFN-γ expression. NRP2 blockade also improved mitochondrial fitness in MDSCs and T cells, impaired neoangiogenesis on MR angiography, and reduced tumor-associated axonogenesis on diffusion tensor imaging tractography (figure 1). In vivo inhibition of NRP2 significantly prolonged survival in both primary and recurrent GBM models (P<0.0001) (figure 2).Conclusions NRP2+ MDSCs serve as key facilitators of tumor-directed axonogenesis in GBM through coordinated neuroimmune signaling. To date, this is the first description of an immune cell-mediated role in promoting neuronal-glioma interactions. Targeting this pathway disrupts neuron-tumor crosstalk, decreases immunosuppression, and offers a promising therapeutic avenue that leverages principles in immunology and cancer neuroscience.Ethics Approval Human subjects were de-identified and obtained through our department’s tissue consent procedure, which is approved on our IRB protocolAbstract 1243 Figure 1Primary GBM efficacyAbstract 1243 Figure 2Recurrent GBM efficacy",
  "authors": [
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "John H Choi"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Ryan Nitta"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Lily Kim"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "John Klich"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Caren Wu"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Ethan Schonfeld"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Andrew Tran"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Si Yeon Lee"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Kwang Bog Cho"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Gordon Li"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Eric Appel"
    },
    {
      "affiliations": [
        "Stanford Hospital, Palo Alto, CA, USA"
      ],
      "name": "Michael Lim"
    }
  ],
  "title": "1243 Tumor associated myeloid cells facilitate cancer axonogenesis in glioblastoma",
  "uid": "21d2435d-a045-5ddb-aef9-f1e4a4bde641"
}