Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy

Cai, Sanjun; Chen, Ziyi; Wang, Yingjie; Wang, Min; Wu, Junye; Tong, Yuhong; Chen, Lanlan; Lü, Chunhua; Yang, Huanghao

doi:10.7150/thno.45777

Cited by 44 publications

(30 citation statements)

References 45 publications

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“…The key to improve the anti-PD-1 therapy is the formation of combination therapies (39). Accumulating evidences have indicated that altered PD-L1 expression by small molecules can modify the efficacy of anti-PD-1 therapy in preclinical phase (40)(41)(42). In this work, as Figure 7 shows, we found that DSF could upregulate PD-L1 expression through hypomethylating IRF7 via inhibition of DNMT1 activity and expression, and improve the anti-PD-1 therapy by modulating TIME.…”

Section: Discussionmentioning

confidence: 99%

Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

Zheng

Liu

et al. 2021

Front. Oncol.

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Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, disulfiram (DSF) kills tumor cells via regulating multiple signaling pathways and transcription factors. However, its effect on tumor immune microenvironment (TIME) remains unclear. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through bioinformatics analysis, we found that DNMT1 was highly expressed in TNBC tissue and PD-L1 was negatively correlated with IRF7 expression. DSF reduced DNMT1 expression and activity, and hypomethylated IRF7 promoter region resulting in upregulation of IRF7. Furthermore, we found DSF enhanced PD-L1 expression via DNMT1-mediated IRF7 hypomethylation. In in vivo experiments, DSF significantly improved the response to anti-PD-1 antibody (Ab) in 4T1 breast cancer mouse model. Immunohistochemistry staining showed that granzyme B+ and CD8+ T cells in the tumor tissues were significantly increased in the combination group. By analyzing the results of the tumor tissue RNA sequencing, four immune-associated pathways were significantly enriched in the DSF joint anti-PD-1 Ab group. In conclusion, we found that DSF could upregulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate TIME to show much better antitumor efficacy than monotherapy.

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Section: Discussionmentioning

confidence: 99%

Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

Zheng

Liu

et al. 2021

Front. Oncol.

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“…Metformin attenuated PD-L1 expression by phosphorylating oncogene YAP1 and inhibiting its entry in the nucleus, subsequently inducing the Hippo signaling pathway in CRC [ 243 ]. Further, Nanodrug (MS NPs), self-assembled from metformin and anticancer agent 7-ethyl-10-hydroxycamptothecin (SN38), was developed to suppress PD-L1 expression, enhancing the anti-tumor effect of combined immunotherapy and chemotherapy in breast cancer [ 244 ]. PARP inhibitor (PARPi) upregulated PD-L1 expression by inactivating GSK3β and enhancing immunosuppression in breast cancer [ 245 ].…”

Section: Potential Drug Intervention On Pd-l1 and Ctla-4mentioning

confidence: 99%

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang

Dai

et al. 2021

J Exp Clin Cancer Res

270

168

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The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

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“…administration of anti-PD-L1 antibody, intraperitoneal ( i.p. ) injection may decrease the systemic exposure to antibodies and further attenuate the acute systemic immune response to reduce animal lethality 66 . The mice were assigned to five treatment groups: (1) saline, (2) US, (3) anti-PD-L1, (4) MLipRIR NPs + US and (5) MLipRIR NPs + US + anti-PD-L1.…”

Section: Resultsmentioning

confidence: 99%

Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem

et al. 2021

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Introduction: An imbalance in redox homeostasis consistently inhibits tumor cell proliferation and further causes tumor regression. Thus, synchronous glutaminolysis inhibition and intracellular reactive oxygen (ROS) accumulation cause severe redox dyshomeostasis, which may potentially become a new therapeutic strategy to effectively combat cancer. Methods: Mitochondrial-targeting liposomal nanoparticles (abbreviated MLipRIR NPs) are synthesized by the encapsulation of R162 (inhibitor of glutamate dehydrogenase 1 [GDH1]) and IR780 (a hydrophobic sonosensitizer) within the lipid bilayer, which are exploited for ultrasound (US)-activated tumor dyshomeostasis therapy reinforced by immunogenic cell death (ICD). Results: R162 released from MLipRIR NPs disrupts the glutaminolysis pathway in mitochondria, resulting in downregulated enzymatic activity of glutathione peroxidase (GPx). In addition, loaded IR780 can generate high levels of ROS under US irradiation, which not only interrupts mitochondrial respiration to induce apoptosis but also consumes local glutathione (GSH). GSH depletion accompanied by GPx deactivation causes severe ferroptosis of tumor cells through the accumulation of lipid peroxides. Such intracellular redox dyshomeostasis effectively triggers immunogenic cell death (ICD), which can activate antitumor immunity for the suppression of both primary and distant tumors with the aid of immune checkpoint blockade. Conclusions: Taking advantage of multimodal imaging for therapy guidance, this nanoplatform may potentiate systemic tumor eradication with high certainty. Taken together, this state-of-the-art paradigm may provide useful insights for cancer management by disrupting redox homeostasis.

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Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy

Cited by 44 publications

References 45 publications

Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem

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