Fig. 1
From: Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma
The immunosuppressive mechanism of glioblastoma microenvironment. The immunosuppressive microenvironment of glioblastoma is composed of a variety of immunosuppressive cells and cytokines. The effective immune cells mainly include CD4+ T cells, CD8+ T cells, NK cells, and tumour-inhibiting M1-TAMs, which are in a state of exhaustion or suppression in the microenvironment. The immunosuppressive cells mainly include Tregs, tumourigenic M2-TAMs, myeloid cells, and MDSCs. Tumour cells express high levels of PD-L1 and IDO, downregulate MHC and costimulatory molecules, express/activate STAT3, cause PTEN loss, then reduce the immunogenicity and induce recruitment of Tregs. Tumour cells secrete MICA/B, IL-10, TGF-β, and HLA-E to recruit Tregs and inhibit both T cell and NK cell activity. Through the secretion of diverse chemokines and other factors, such as CCL2, CSF1, MCP-3, CXCL12, CX3CL1, GDNF, ATP, and GM-CSF, the paracrine network signalling between glioblastoma and the TAMs attracts myeloid cells and infiltrates Tregs. Furthermore, tumour cells secrete immunomodulatory cytokines that polarize TAMs to the immunosuppressive M2 phenotype. Immunosuppressive cells, including M2-TAMs, myeloid cells, and MDSCs, secrete a variety of cytokines (IL-6, IL-10, IL-4Ra, FasL, CCL2, PGE2, EGF, VEGF, and MMP9) to suppress the function of cytotoxic T lymphocytes (CTLs) and promote the progression of tumour cells. In addition, Tregs downregulate IL-2 production, inhibit IFN-γ production, and upregulate TH2 cytokine secretion to inhibit T cell function. TAM: tumor-associated macrophage; MDSC: myeloid-derived suppressor cell; CCL2: chemokine ligand 2; CSF1: colony-stimulating factor 1; MCP-3: monocyte-chemotactic protein-3; GDNF: glial cell-derived neurotrophic factor; GM-CSF: granulocyte-macrophage colony-stumulating factor; KIR: killer cell Ig-like receptor; GITR: glucocorticoid-induced TNFR-related protein; STAT3: signal transducers and activators of transcription; PGE2: prostaglandin E2; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; MMP9: matrix metalloproteinase-9