Abstract
Simple SummaryThe present study showed that a prescribed psychotropic medicine paliperidone inhibits GBM growth and prolongs survival in mouse brain tumor model and decreased the programmed death ligand 1 expression. Using the 3D co-culture also found that dopamine receptor D2 regulates the interaction of GBM-macrophage-induced PD-L1 expression in GBMs. In addition, the expression of DRD2 and PD-L1 in GBM modulates tumor-associated macrophage polarization. Our results also indicated that there is a contact-independent mechanism of PD-L1 induction in GBM upon interaction between GBM and monocytes. The present study also found that the interaction of GBM-macrophage-enhanced PD-L1 expression in GBM occurred by modulating the ERK and STAT3 signaling pathways. In addition, the inhibition of DRD2 reduces the upregulation of PD-1 expression, and it is regulating signaling in GBM.A previous study from our group reported that monocyte adhesion to glioblastoma (GBM) promoted tumor growth and invasion activity and increased tumor-associated macrophages (TAMs) proliferation and inflammatory mediator secretion as well. The present study showed that prescribed psychotropic medicine paliperidone reduced GBM growth and immune checkpoint protein programmed death ligand (PD-L)1 expression and increased survival in an intracranial xenograft mouse model. An analysis of the database of patients with glioma showed that the levels of PD-L1 and dopamine receptor D (DRD)2 were higher in the GBM group than in the low grade astrocytoma and non-tumor groups. In addition, GFP expressing GBM (GBM-GFP) cells co-cultured with monocytes-differentiated macrophage enhanced PD-L1 expression in GBM cells. The enhancement of PD-L1 in GBM was antagonized by paliperidone and risperidone as well as DRD2 selective inhibitor L741426. The expression of CD206 (M2 phenotype marker) was observed to be markedly increased in bone marrow-derived macrophages (BMDMs) co-cultured with GBM. Importantly, treatment with paliperidone effectively decreased CD206 and also dramatically increased CD80 (M1 phenotype marker) in BMDMs. We have previously established a PD-L1 GBM-GFP cell line that stably expresses PD-L1. Experiments showed that the expressions of CD206 was increased and CD80 was mildly decreased in the BMDMs co-cultured with PD-L1 GBM-GFP cells. On the other hands, knockdown of DRD2 expression in GBM cells dramatically decreased the expression of CD206 but markedly increased CD80 expressions in BMDMs. The present study suggests that DRD2 may be involved in regulating the PD-L1 expression in GBM and the microenvironment of GBM. Our results provide a valuable therapeutic strategy and indicate that treatments combining DRD2 antagonist paliperidone with standard immunotherapy may be beneficial for GBM treatment.
Highlights
Glioblastoma (GBM) is considered the most deadly brain tumors because of its aggressive invasive growth and its resistance to chemotherapy and radiotherapy [1,2], and the average life expectancy of GBM patients is only approximately 15 months [3]
Analysis of the glioma in mouse brain showed that mRNA levels of PD-L1 were lower in the paliperidone treatment group than in the vehicle control group (Figure 1E)
The present study reported that there is a cell–cell contact-independent mechanism of PD-L1 expression in GBM underlying the interaction between GBM and tumor-associated macrophages (TAMs), and DRD2 is involved in modulating the PD-L1 induction between GBM and its tumor microenvironment
Summary
Glioblastoma (GBM) is considered the most deadly brain tumors because of its aggressive invasive growth and its resistance to chemotherapy and radiotherapy [1,2], and the average life expectancy of GBM patients is only approximately 15 months [3]. In histological analysis of GBM, a heterogeneous cellular composition of neoplastic glioma cells and non-neoplastic cells forms the tumor microenvironment that composes of brain-resident microglia, infiltrating monocytes/macrophages, reactive astrocytes, and other immune cell infiltrates [4]. Microglia and circulating monocytes/macrophages have been found to constitute up to 30% of tumor mass in both human and murine GBMs [5,6]. Accumulating studies indicated that non-neoplastic cells in the tumor microenvironment are important for the maintenance of cancer growth and the responses to therapies. Monocytes belong to the mononuclear phagocyte system and arise from hematopoietic stem cells in the bone marrow that are released during infection and inflammation and differentiated into macrophages, which functions to maintain immunity homeostasis [8].
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