Lung cancer is one of the common malignant cancers worldwide. Immune checkpoint inhibitor (ICI) therapy has improved survival of lung cancer patients. However, ICI therapy leads to adaptive immune resistance and displays resistance to PD-1/PD-L1 blockade in lung cancer, leading to less immune response of lung cancer patients. Tumor microenvironment (TME) is an integral tumor microenvironment, which is involved in immunotherapy resistance. Nanomedicine has been used to enhance the immunotherapy in lung cancer. In this review article, we described the association between TME and immunotherapy in lung cancer. We also highlighted the importance of TME in immunotherapy in lung cancer. Moreover, we discussed how nanoparticles are involved in regulation of TME to improve the efficacy of immunotherapy, including Nanomedicine SGT-53, AZD1080, Nanomodulator NRF2, Cisplatin nanoparticles, Au@PG, DPAICP@ME, SPIO NP@M-P, NBTXR3 nanoparticles, ARAC nanoparticles, Nano-DOX, MS NPs, Nab-paclitaxel, GNPs-hPD-L1 siRNA. Furthermore, we concluded that targeting TME by nanoparticles could be helpful to overcome resistance to PD-1/PD-L1 blockade in lung cancer.

2021-02-01·Biomaterials1区 · 工程技术

Immune checkpoint inhibition in syngeneic mouse cancer models by a silicasome nanocarrier delivering a GSK3 inhibitor

1区 · 工程技术

Article

作者: Allen, Sean D ; Liao, Yu-Pei ; Chang, Chong Hyun ; Jiang, Jinhong ; Liu, Xiangsheng ; Nel, Andre E ; Meng, Huan

Checkpoint blocking antibodies that interfere in the PD-1/PD-L1 axis provide effective cancer immunotherapy for tumors that are immune inflamed or induced to become "hot". It has also been demonstrated that a small molecule inhibitor of the signaling hub kinase GSK3 can interfere in the PD-1/PD-L1 axis in T-cells by suppressing PD-1 expression. This provides an alternative approach to intervening in the PD-1/PD-L1 axis to provide cancer immunotherapy. In this communication, we demonstrate the remote loading of GSK3 inhibitor AZD1080 into the porous interior of mesoporous silica nanoparticles coated with a lipid bilayer (a.k.a. silicasomes). In a MC38 colon cancer model, intravenous injection (IV) of silicasome-encapsulated AZD1080 significantly improved biodistribution and drug delivery to the tumor site. The improved drug delivery was accompanied by cytotoxic MC38 tumor cell killing by perforin-releasing CD8⁺ T-cells, exhibiting reduced PD-1 expression. IV injection of encapsulated AZD1080 also resulted in significant tumor shrinkage in other syngeneic mouse tumor models, including another colorectal tumor (CT26), as well as pancreas (KPC) and lung (LLC) cancer models. Not only was the therapeutic efficacy of encapsulated AZD1080 similar or better than anti-PD-1 antibody, but the treatment was devoid of treatment toxicity. These results provide proof-of-principal demonstration of the feasibility of using encapsulated delivery of a GSK3 inhibitor to provide cancer immunotherapy, with the possibility to be used as a monotherapy or in combination with chemotherapy or other immunomodulatory agents.

2016-05-10·Oncotarget

The role of glycogen synthase kinase-3β (GSK-3β) in endometrial carcinoma: A carcinogenesis, progression, prognosis, and target therapy marker

Article

作者: Chen, Shuo ; Zhao, Yang ; Sun, Kai-Xuan ; Zong, Zhi-Hong ; Liu, Bo-Liang

PURPOSEGlycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase involved in cancer development. Herein, we demonstrated the role of GSK-3β in endometrial cancer (EC) and identified new therapeutic targets.RESULTSGSK-3β was overexpressed in EC tissues, and was positively correlated with International Federation of Gynecology and Obstetrics (FIGO) staging, dedifferentiation, and myometrial infiltration depth. Besides, GSK-3β overexpression predicted lower cumulative and relapse-free survival rate. si-GSK-3β transfection suppressed cell proliferation, migration, invasion, and promoted cell apoptosis through downregulating NF-kB, Cyclin D1 and MMP9 expression whereas upregulating P21 expression. Bioinformatic predictions and dual-luciferase reporter assays showed that GSK-3β was a possible target of miR-129. MiR-129 transfection reduced GSK-3β expression, and exhibited the same trend as si-GSK-3β transfection in cell function experiments. The nude mouse xenograft assay showed that miR-129 overexpression may suppress tumor growth through downregulating GSK-3β expression. Further studies showed that AZD1080, a GSK-3β inhibitor, could also inhibit EC cell proliferation, migration and invasion, while induced cell apoptosis through modulating relevant genes downstream of GSK-3β signaling.EXPERIMENTAL DESIGNGSK-3β expression was determined in EC tissue and normal endometrial tissues by immunohistochemistry. After GSK-3β down-regulation by si-GSK-3β, microRNA-129 mimic transfection or GSK-3β inhibitor exposure, EC cell phenotypes and related molecules were examined.CONCLUSIONSOur results demonstrate for the first time that GSK-3β may be a novel and important therapeutic target for the treatment of endometrial carcinoma. GSK-3β inhibitor AZD1080 may be an effective drug for treating endometrial carcinoma.

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床1期	-	阿斯利康制药有限公司	-
阿尔茨海默症	临床1期	英国	AstraZeneca PLC	-
肌萎缩侧索硬化	临床1期	英国	The University of Sheffield	-