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

Cancer cell 2025

Gao J, Gu D, Yang K, Zhang J, Lin Q, Yuan W, Zhu X, Dixit D, Gimple RC, You H, Zhang Q, Shi Z, Fan X, Wu Q, Lu C, Cheng Z, Li D, Zhao L, Xue B, Zhu Z, Zhu Z, Yang H, Zhao N, Gao W, Lu Y, Shao J, Cheng C, Hao D, Yang S, Chen Y

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.

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