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

in Cancer cell by Jiancheng Gao, Danling Gu, Kailin Yang, Junxia Zhang, Qiankun Lin, Wei Yuan, Xu Zhu, Deobrat Dixit, Ryan C Gimple, Hao You, Qian Zhang, Zhumei Shi, Xiao Fan, Qiulian Wu, Chenfei Lu, Zhangchun Cheng, Daqi Li, Linjie Zhao, Bin Xue, Zhu Zhu, Zhe Zhu, Hui Yang, Ningwei Zhao, Wei Gao, Yingmei Lu, Junfei Shao, Chuandong Cheng, Dapeng Hao, Shuo Yang, Yun Chen, Xiaoming Wang, Chunsheng Kang, Jing Ji, Jianghong Man, Sameer Agnihotri, Qianghu Wang, Fan Lin, Xu Qian, Stephen C Mack, Zhibin Hu, Chaojun Li, Michael D Taylor, Yan Li, Nu Zhang, Jeremy N Rich, Yongping You, Xiuxing Wang

TLDR

  • This study reveals that plasma cells play a critical role in glioblastoma development and progression, and identifies potential therapeutic targets for treatment.

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.

Overview

  • The study investigates the role of plasma cells (PCs) in glioblastoma, a highly aggressive primary brain tumor.
  • The study uses single-cell RNA and B cell receptor sequencing to analyze tumor-infiltrating B-lineage cells.
  • The primary objective is to understand the significance of PCs in glioblastoma development and progression.

Comparative Analysis & Findings

  • The study finds that plasma cells (PCs) are aberrantly enriched in the glioblastoma-infiltrating B-lineage population.
  • PCs exhibit low levels of somatic hypermutation and are associated with poor prognosis.
  • The IgG-FcγRIIA-AKT-mTOR axis is identified as a key mechanism for GSC proliferation stimulated by IgG secreted by PCs.

Implications and Future Directions

  • The study's findings suggest that combinatorial targeting of both tumor cell-intrinsic and microenvironmental dependencies may be an effective therapeutic strategy.
  • Future studies could investigate the potential of immune checkpoint inhibitors as a means to target GSCs and inhibit their proliferation.
  • Understanding the mechanisms underlying GSC recruitment and signaling may lead to the development of novel therapeutic approaches for glioblastoma treatment.
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