Phagocytosis of Glioma Cells Enhances the Immunosuppressive Phenotype of Bone Marrow- Derived Macrophages

Tumor-associated macrophages (TAM) play a crucial role in immunosuppression. However, how TAMs are transformed into immunosuppressive phenotypes and influence the tumor micro -environment (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 pro-liferation 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 immunosuppres-sion in GBM.

Automated summary

Tumor-associated macrophages (TAM) play a crucial role in immunosuppression, but how TAMs are transformed and influence the tumor microenvironment (TME) is not fully understood. In this study, researchers identified a subset of TAMs termed double-positive TAMs that co-expressed macrophage and tumor markers. These double-positive TAMs had immunosuppressive phenotypes and were transformed into M2-like macrophages, expressing immune-checkpoint proteins and suppressing T cell proliferation. This study sheds light on the processes driving TAM-mediated immunosuppression in glioblastoma.