Phagocytosis of Glioma Cells Enhances the Immunosuppressive Phenotype of Bone Marrow–Derived Macrophages
Min Wu, Lingxiang Wu, Wei Wu, Mengyan Zhu, Jianyu Li, Ziyu Wang, Jie Li, Rong Ding, Yuan Liang, Liangyu Li, Tingting Zhang, Bin Huang, Yun Cai, Kening Li, Lu Li, Rui Zhang, Baoli Hu, Fan Lin, Xiuxing Wang, Siyuan Zheng, Jian Chen, Yongping You, Tao Jiang, Junxia Zhang, Hongshan Chen, Qianghu Wang
Abstract
Tumor-associated macrophages (TAM) play a crucial role in immunosuppression. However, how TAMs are transformed into immunosuppressive phenotypes and influence the tumor microenvironment (TME) is not fully understood. Here, we utilized single-cell RNA sequencing and whole-exome sequencing data of glioblastoma (GBM) tissues and identified a subset of TAMs dually expressing macrophage and tumor signatures, which were termed double-positive TAMs. Double-positive TAMs tended to be bone marrow-derived macrophages (BMDM) and were characterized by immunosuppressive phenotypes. Phagocytosis of glioma cells by BMDMs in vitro generated double-positive TAMs with similar immunosuppressive phenotypes to double-positive TAMs in the GBM TME of patients. The double-positive TAMs were transformed into M2-like macrophages and drove immunosuppression by expressing immune-checkpoint proteins CD276, PD-L1, and PD-L2 and suppressing the proliferation of activated T cells. Together, glioma cell phagocytosis by BMDMs in the TME leads to the formation of double-positive TAMs with enhanced immunosuppressive phenotypes, shedding light on the processes driving TAM-mediated immunosuppression in GBM. SIGNIFICANCE: Bone marrow-derived macrophages phagocytose glioblastoma cells to form double-positive cells, dually expressing macrophage and tumor signatures that are transformed into M2-like macrophages and drive immunosuppression.