Paliperidone Inhibits Glioblastoma Growth in Mouse Brain Tumor Model and Reduces PD-L1 Expression
| Autor: | Chao-Wei Chen, Chingju Lin, Yu-Shu Liu, Yun-Chen Hsieh, Hui-Jung Lin, Chia-Huei Lin, Dah-Yuu Lu, Sheng-Wei Lai, Bor-Ren Huang, Ching-Kai Shen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
PD-L1
Cancer Research medicine.medical_treatment Tumor-associated macrophage urologic and male genital diseases Article tumor-associated macrophage Glioma medicine Paliperidone RC254-282 Gene knockdown biology Chemistry urogenital system glioblastoma Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunotherapy medicine.disease Immune checkpoint female genital diseases and pregnancy complications nervous system diseases Oncology Cancer research biology.protein DRD2 paliperidone CD80 medicine.drug |
| Zdroj: | Cancers Volume 13 Issue 17 Cancers, Vol 13, Iss 4357, p 4357 (2021) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers13174357 |
| Popis: | Simple Summary The 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. Abstract 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. |
| Databáze: | OpenAIRE |
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