Infiltrating plasma cells maintain glioblastoma stem cells through IgG-Tumor binding

Cancer Cell. 2025 Jan 13;43(1):122-143.e8. doi: 10.1016/j.ccell.2024.12.006. Epub 2025 Jan 2.

Abstract

Glioblastoma is a highly aggressive primary brain tumor with glioblastoma stem cells (GSCs) enforcing the intra-tumoral hierarchy. Plasma cells (PCs) are critical effectors of the B-lineage immune system, but their roles in glioblastoma remain largely unexplored. Here, we leverage single-cell RNA and B cell receptor sequencing of tumor-infiltrating B-lineage cells and reveal that PCs are aberrantly enriched in the glioblastoma-infiltrating B-lineage population, experience low level of somatic hypermutation, and are associated with poor prognosis. PCs secrete immunoglobulin G (IgG), which stimulates GSC proliferation via the IgG-FcγRIIA-AKT-mTOR axis. Disruption of IgG-FcγRIIA paracrine communication inhibits GSC proliferation and self-renewal. Glioblastoma-infiltrating PCs are recruited to GSC niches via CCL2-CCR2 chemokine program. GSCs further derive pro-proliferative signals from broadly utilized monoclonal antibody-based immune checkpoint inhibitors via FcγRIIA signaling. Our data generate an atlas of B-lineage cells in glioblastoma with a framework for combinatorial targeting of both tumor cell-intrinsic and microenvironmental dependencies.

Keywords: FcγRIIA; glioblastoma; glioblastoma stem cell; plasma cell; single-cell B cell receptor-seq; single-cell RNA-seq.

MeSH terms

  • Animals
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / immunology
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Glioblastoma* / genetics
  • Glioblastoma* / immunology
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Immunoglobulin G* / immunology
  • Immunoglobulin G* / metabolism
  • Mice
  • Neoplastic Stem Cells* / immunology
  • Neoplastic Stem Cells* / metabolism
  • Neoplastic Stem Cells* / pathology
  • Plasma Cells* / immunology
  • Plasma Cells* / metabolism
  • Receptors, IgG / immunology
  • Receptors, IgG / metabolism
  • Signal Transduction
  • Tumor Microenvironment / immunology

Substances

  • Immunoglobulin G
  • Receptors, IgG