Abstract
BackgroundThe immunosuppressive tumour microenvironment is a critical factor in the initiation and progression of glioblastoma (GBM), which is characterized by an abundance of tumour-associated macrophages (TAMs) but a paucity of infiltrating T cells. In this research, we studied whether epithelial membrane protein 3 (EMP3) plays a crucial role in immune modulation in GBM.MethodsTCGA and CGGA transcriptomic profiles of wild-type IDH1 GBM were used for bioinformatic analysis. The role of EMP3 in GBM was validated through in vivo and in vitro experiments. Human GBM specimens were collected and evaluated using immunofluorescence analysis.ResultsEMP3 was associated with immunosuppression in GBM. Elevated EMP3 in GBM areas was accompanied by high expression of PD-L1 and abundant M2 TAM recruitment but a lake of T cell infiltration. We found that EMP3 was a potent protein in M2 TAM polarization and recruitment that impaired the ability of GBM cells to secrete CCL2 and TGF-β1. Furthermore, EMP3 suppressed T cell infiltration into GBM tumours by inhibiting the secretion of CXCL9 and CXCL10 by macrophages and led to an effective response to anti-PD1 therapy.ConclusionsEMP3 is thus a critical immunosuppressive factor for recruiting TAMs in GBM and suppressing intratumoural T cell infiltration to facilitate tumour progression and is a potential therapeutic target.
Highlights
The immunosuppressive tumour microenvironment is a critical factor in the initiation and progression of glioblastoma (GBM), which is characterized by an abundance of tumour-associated macrophages (TAMs) but a paucity of infiltrating T cells
BV-2 cells incubated with supernatants from GL261 cells showed positive staining for both CD86 and CD206, indicating that M2 TAMs could be polarized by epithelial membrane protein 3 (EMP3) (Fig. 2b)
The number of M2 TAMs infiltrating GBM tumours was reduced in the EMP3_KO group (Fig. 2f). These results reveal that GBM-derived EMP3 plays critical roles in promoting M2 TAM recruitment and polarization
Summary
The immunosuppressive tumour microenvironment is a critical factor in the initiation and progression of glioblastoma (GBM), which is characterized by an abundance of tumour-associated macrophages (TAMs) but a paucity of infiltrating T cells. M2 TAMs are the main TAMs in most malignant tumours and play important roles in immunosuppression and treatment resistance [2, 3]. TAM infiltration within the tumour microenvironment (TME) of human GBM patients. M2 TAMs are recruited to the TME and are emerging as important mediators of adaptive resistance to immune attack. In GBM patients, it is common for the numbers of CD4+ and CD8+ T cells to decrease within the tumour and in the circulation [4, 5]. With the expansion of indications for checkpoint inhibitors, an increasing number of patients are receiving these drugs. Despite the durable clinical response to antibodies that block PD-1 seen in
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