JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2022
·
IF 6.117
Qi Zhang,Wanshuang Cao,Chenying Yang,Lixia Hong,Shanshan Geng,Hongyu Han,Caiyun Zhong
The PD-1/PD-L1 immune checkpoint blockade therapy has shown revolutionary efficacy in the treatment of multiple cancers including gastric cancer. Isothiocyanates play important roles in cancer cell suppression and immunomodulation . However, the effects of isothiocyanates on immune checkpoint inhibitors are poorly understood in gastric cancer. The influence of three major isothiocyanates (sulforaphane, phenylethyl isothiocyanate, and benzhydryl isothiocyanate) on gastric cancer cell growth and PD-L1 expression was investigated. Syngeneic mouse models were administered by isothiocyanates and anti-PD-L1 monoclonal antibody , and the anti-tumor effects were assessed. The expression of PD-L1, proportion of lymphocytes and serum cytokine levels were detected to explore the underlying mechanisms. We found that PD-L1 expression was significantly induced by isothiocyanates which was associated with TAp63α up-regulation. We further revealed that TAp63α promoted PD-L1 through transcriptional activation . Combination treatment of isothiocyanates and anti-PD-L1 therapy weakened the sensitivity of gastric cancer cells to anti-PD-L1 drug. Moreover, in vivo studies illustrated that the interference effects of isothiocyanates on anti-PD-L1 antibody were related to PD-L1 expression and decreased infiltrating T lymphocytes in tumor bearing mouse hosts. Our findings provide novel insights as isothiocyanates could interfere with the successful application of immunotherapy in gastric cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Saijun Wang,Zaigang Zhou,Rui Hu,Mingyue Dong,Xiaobo Zhou,Siyan Ren,Yi Zhang,Chengxun Chen,Ruoyuan Huang,Man Zhu,Wanying Xie,Ling Han,Jianliang Shen,Congying Xie
At present, radiotherapy (RT) still acquires limited success in clinical due to the lessened DNA damage under hypoxia and acquired immune tolerance owing to the amplified programmed death ligand-1 (PD-L1) expression. Incredibly, intracellular PD-L1 expression depression is proven to better sensitize RT by inhibiting DNA damage repair. However, the disability of the clinically used antibodies in disrupting the extracellular PD-L1function still limits the effectiveness of radio-immunotherapy. Therefore, better PD-L1 regulation strategies are still urgently needed to better sensitize radio-immunotherapy. Hence, for this purpose, TPP-LND is synthesized by linking mitochondrial-targeted triphenylphosphine cations (TPP + ) to the antineoplastic agent lonidamine (LND), which significantly reduces the dose needed for LND to induce effective oxidative phosphorylation inhibition (2 vs 300 µ M ). Then, TPP-LND is wrapped with liposomes to form TPP-LND@Lip nanoparticles. By doing this, TPP-LND@Lip nanoparticles can sensitize RT by reversing the hypoxic microenvironment of tumors to generate more DNA damage and reducing the expression of PD-L1 via enhancing the adenosine 5′-monophosphate-activated protein kinase activation. As expected, these well-designed economical TPP-LND@Lip nanoparticles are more effective than conventional anti-PD-L1 antibodies to some extent.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·Vol. 12
·期 17
·2300110
·
IF 10
Shuaiying Wu,Jianzhong Zhang,Jie Pan,Shuang Bai,Ziying Wang,Yulun Chen,Dazhuang Xu,Yibo An,Chao Liu,Chengchao Chu,Qixuan Dai,Lai Jiang,Zhixiang Lu,Gang Liu
It is an engaging program for tumor treatment that rationalizes the specific microenvironments, activation of suppressed immune system (immune resistance/escape reversion), and synergistic target therapy. Herein, a biomimetic nanoplatform that combines oxidative stress with genetic immunotherapy to strengthen the therapeutic efficacy is developed. Ru-TePt nanorods, small interfering RNA (PD-L1 siRNA), and biomimetic cellular membrane vesicles with the targeting ability to design a multifunctional Ru-TePt@siRNA-MVs system are rationally integrated. Notably, the Fenton-like activity significantly enhances Ru-TePt nanorods sonosensitization, thus provoking stronger oxidative stress to kill cells directly. Meanwhile, immunogenic cell death is triggered to secrete numerous cytokines and activate T cells. The effective catalase characteristics of Ru-TePt enable the in situ oxygen-producing pump to improve tumor oxygen level and coordinately strengthen the therapeutic effect of SDT followed. More importantly, anti-PD-L1-siRNA mediated immune checkpoint silence of the PD-L1 gene creates an environment conducive to activating cytotoxic T lymphocytes, synergistic with boosted reactive oxygen species-triggered antitumor immune response. The experimental results in vitro and in vivo reveal that the Ru-TePt@siRNA-MVs nanosystems can effectively activate the oxidative stress-triggered immune response and inhibit PD-1/PD-L1 axis-mediated immune resistance. Consequently, this orchestrated treatment paradigm provides valuable insights for developing potential oxidative stress and genetic immunotherapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Ze Lin,Yuan Xiong,Weilin Meng,Yiqiang Hu,Lili Chen,Lang Chen,Hang Xue,Adriana C. Panayi,Wu Zhou,Yun Sun,Faqi Cao,Guodong Liu,Liangcong Hu,Chenchen Yan,Xudong Xie,Chuanchuan Lin,Kaiyong Cai,Qian Feng,Bobin Mi,Guohui Liu
A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of [email protected] systems for bone fracture therapy through immune inhibitory effects.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2020
·
IF 5.893
Linxin Teng,Kaiyuan Wang,Weiping Chen,Yun-shan Wang,Lei Bi
Traditional Chinese medicine (TCM) plays a vital part in cancer treatment due to its unique superiority. Huoxue Yiqi Recipe-2 (HYR-2) was supposed to have therapeutic effect on lung cancer, which came from Ze Qi Decoction in one of the four great classics of TCM called "Synopsis of Prescriptions of the Golden Chamber". Network pharmacology demonstrated that the targets of active components from HYR-2 were significantly enriched in the signaling pathways, which were closely associated with non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1). Then, data about NSCLC was downloaded from Gene Expression Omnibus database (GEO). The Cancer Genome Atlas (TCGA) and DisGeNET was analyzed by bioinformatics, and 214 biomarkers for NSCLC were obtained, containing 14 targets of active components from HYR-2 (which were significantly enriched in the PD-L1 related signaling pathway). In vivo and in vitro experiments showed that HYR and HYR-2 could inhibit the growth of lung cancer and down-regulate the expression of PD-L1, which might be related to the blocking effect of HYR-2 on the PI3K/Akt signaling pathway. Furthermore, HYR-2 promoted the transformation of M2 macrophages into M1 macrophages as well. It is deserved to be mentioned that the level of Akkermansia muciniphila was also significantly elevated by HYR-2, which was believed to enhance the therapeutic effect of PD-L1 antibodies. To sum up, HYR-2 might play an anti-lung cancer effect by down-regulating PD-L1 together with up-regulating Akkermansia muciniphila.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2020
·
IF 10.652
Ningning Wang,Yaxin Zhou,Yuwen Xu,Xiaomeng Ren,Shiyao Zhou,Qi Shang,Yue Jiang,Yuxia Luan
Immune checkpoint blockade (ICB) strategy based on suppressing programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has been proved to be promising and effective in cancer immunotherapy. However, its potential risk of immune-related adverse events (irAEs) places stringent requirements on the precise loading of anti-PD-L1 agent in nanomedicine. Precise control of the loading content of anti-PD-L1 antibody is a difficult task since physical encapsulation has inevitable drawbacks like batch-to-bath variation and chemical modification is limited by the low stability of the antibody. Herein, we proposed a molecular engineering strategy to develop the nanomedicine with precise control of anti-PD-L1 agent content by using anti-PD-L1 peptide (APP) as the substitute to anti-PD-L1 antibody. The APP was chemically bonded with a photosensitizer IR780 to obtain IR780-M-APP, a molecule able to self-assemble into nanoparticles (NPs) with a precise APP loading (48.4 wt%) determined by the molecular structure. Specifically, the IR780 moiety in IR780-M-APP NPs endows the nanoparticles with photodynamic therapeutic effect as well as the ability to trigger immunogenic cell death (ICD), while the APP moiety can block the PD-1/PD-L1 pathway for promoting immunotherapy. The proposed photodynamic-immunotherapy nanoplatform not only killed primary tumors directly but also eradicated the metastatic and invasive tumors effectively. The present molecular engineering strategy combined with anti-PD-L1 peptide might provide more opportunities for the design of advanced nanoplatforms for cancer therapy.
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR HUMAN REPRODUCTION
·
2022
·Vol. 28
·期 5
·
IF 4.518
Li Jing,Yan Shumin,Li Qiuju,Huang Yufei,Ji Miaomiao,Jiao Xue,Yuan Ming,Wang Guoyun
Peritoneal macrophages play a significant role in the progression of endometriosis (EM), but their functional differentiation is still unclear, and their phagocytic ability is weak. CD47-signal-regulated protein α (SIRPα) and PD-L1-PD-1 are considered immune checkpoints associated with macrophage phagocytosis. A specific blockade of these two pathways had been shown to increase the phagocytic clearance of cancer cells by macrophages in most cancers. We hypothesized that targeting CD47/PD-L1 in EM could improve the phagocytosis of macrophages, thereby delaying the progression of EM. From localization to quantification, from mRNA to protein, we comprehensively evaluated the expression of CD47 and PD-L1 in EM. We demonstrated that the CD47 expression in ectopic endometrium from patients with EM was significantly increased, but PD-L1 was not. We performed direct co-culture experiments of endometrial stromal cells with macrophages in vitro and in vivo to assess whether ectopic endometrial stromal cells escape macrophage phagocytosis through the CD47-SIRPα signaling pathway. The results showed that targeting CD47 increased the phagocytic capacity of macrophages. Interestingly, we also found that the reduction of CD47 expression promoted apoptosis of endometrial stromal cells. In conclusion, these data suggested that targeting CD47 can effectively target ectopic endometrial stromal cells through a dual mechanism of increased phagocytosis of macrophages and induced apoptosis of ectopic endometrial stromal cells. Thus, immunotherapy based on the CD47-SIRPα signaling pathway has some potential in treating EM, but further mechanistic studies are needed to explore more effective and specific antibodies.
研究领域:
免疫学
·
妇科学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2026
·
IF 17.1
Junyan Zhuang,Ye Chen,Yi Zhang,Yongrui Hai,Renming Fan,Jiarui Dou,Xintong Lu,Wenhui Wang,Bingjie Zhang,Zhuang Hou,Lei Liang,Yang Liu,Gaofei Wei
Introduction Glutamine is a key nutrient that supports tumor cell metabolism, biosynthesis, and proliferation. It also shapes the tumor microenvironment and modulates cell death pathways. Glutamine antagonists have emerged as effective therapeutic agents by both disrupting tumor energy metabolism and enhancing antitumor immune responses. However, recent evidence reveals a paradoxical effect: glutamine deprivation can induce PD-L1 expression on tumor cells, facilitating immune escape and reducing the efficacy of immunotherapies. Objectives This study aims to overcome the immune evasion triggered by glutamine deprivation by developing a dual-functional therapeutic strategy that enhances metabolic stress while simultaneously inhibiting PD-L1 expression. The ultimate goal is to strengthen antitumor immunity and improve therapeutic outcomes. Methods We designed and synthesized a novel prodrug, HB023, by covalently linking a glutamine metabolism inhibitor with JQ1, a well-characterized PD-L1 inhibitor. We evaluated the effects of HB023 on tumor cell pyroptosis, energy metabolism, PD-L1 expression, T cell-mediated cytotoxicity, and macrophage polarization using a combination of in vitro cell-based assays and in vivo tumor models. Results HB023 significantly enhanced glutamine starvation in tumor cells, leading to increased pyroptosis and restricted energy supply. It effectively downregulated PD-L1 expression, which restored T cell cytotoxic activity. Additionally, HB023 induced mitochondrial membrane remodeling in macrophages, promoting M1 polarization and thereby enhancing innate immune responses. These mechanisms cooperatively activated both adaptive and innate antitumor immunity, thereby conferring HB023 with superior antitumor efficacy compared with JQ1, JHU083, or their combination. Conclusion HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Wei Min,Shen Xiao,Fan Xueqi,Li Jiwei,Bai Jingwen
Immune checkpoint blockade is now recognized as a paradigm-shifting cancer therapeutic strategy, whereas there remains difficulty in accurately predicting immunotherapy efficacy by PD-L1 expression. In addition, radiotherapy for cancer patients faces the problem of insufficient dose of radiotherapy at the tumor site while which have been not tolerated by normal tissues. In this study, we created PD-L1 aptamer-anchored spherical nucleic acids (SNAs) with a shell made of PD-L1 aptamer and indocyanine green (ICG) embedded in a mesoporous hafnium oxide nanoparticle core (Hf@ICG-Apt). Upon low pH irradiation in the tumor sites, the nano-system enabled the release of ICG in the high PD-L1 expression tumor to develop a high tumor-to-background ratio of 7.97 ± 0.76 and enhanced the ICG tumor retention to more than 48 h. Moreover, Hf@ICG-Apt improved radiation therapy (RT) when combined with radiation. Notably, Hf@ICG-Apt showed scarcely any systemic toxicity in vivo. Overall, this research offered a novel approach for applying reliable monitoring of PD-L1 expression and localization and robust RT sensitization against cancer with good biosafety.
研究领域:
癌症治疗
·
纳米技术
·
医学成像
·
放射生物学
·
免疫疗法
✓ 已验证
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-13
·
IF 16.6
Wang Shenqiang,Zhang Ying,Wang Yanfang,Yang Yinxian,Zhao Sheng,Sheng Tao,Zhang Yuqi,Gu Zhen,Wang Jinqiang,Yu Jicheng
Immune checkpoints play key roles in maintaining self-tolerance. Targeted potentiation of the checkpoint molecule PD-L1 through in situ manipulation offers clinical promise for patients with autoimmune diseases. However, the therapeutic effects of these approaches are often compromised by limited specificity and inadequate expression. Here, we report a two-step dual-anchor coupling strategy for enhanced immobilization of PD-L1 on target endogenous cells by integrating bioorthogonal chemistry and physical insertion of the cell membrane. In both type 1 diabetes and rheumatoid arthritis mouse models, we demonstrate that this approach leads to elevated and sustained conjugation of PD-L1 on target cells, resulting in significant suppression of autoreactive immune cell activation, recruitment of regulatory T cells, and systematic reshaping of the immune environment. Furthermore, it restores glucose homeostasis in type 1 diabetic mice for over 100 days. This specific in situ bioengineering approach potentiates the functions of PD-L1 and represents its translational potential.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2023
·
IF 8.4
Mingli Ye,Qi Niu,Lu Yan,Jianzhou Feng,Lingling Wu,Xiaoya Hu,Qin Xu,Yun Shu
Programmed death ligand 1 (PD-L1) of tumor-derived extracellular vesicles (T-EVs) is an important biomarker to predict immunotherapy response. The traditional bioassays of T-EVs PD-L1 are limited by the detection specificity because of the distribution of the signals by PD-L1 from nontumor-derived EVs, which leads to unsatisfactory predictive accuracy. In this work, we developed a simple and ultrasensitive method for the quantification of T-EVs PD-L1 by using the lipid bilayer magnetic interface as the isolation and enrichment carrier along with hybridization chain reaction (HCR) for signal amplification in a paper-based device. First, magnetic beads were covered by liposome bilayers and then anchored with the cholesterol modified epithelial cell adhesion molecule (EpCAM) aptamer to construct a fluid multivalent magnetic interface and realize the high-performance isolation of T-EVs. Moreover, the biosensor relied on the PD-L1 aptamer to initiate the HCR of EVs. Benefiting from the high isolation ability of the lipid bilayer magnetic interface and the high signal amplification ability of HCR, the dual-aptamer-based biosensor is capable of highly sensitive detection of T-EVs with a detection limit as low as 5.0 EVs·µL −1 in a paper-based device. Overall, the paper-based lipid bilayer magnetic interface biosensor not only can serve as an alternative tool for predicting the immunotherapy response but also displays great potential in point-of-care disease diagnosis.
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yanyun Hao,Hui Li,Xiaoyan Ge,Yang Liu,Jialin Yin,Xia Li,Yutong Liu,Hongfei Chen,Lingling Huang,Jing Zou,Shiying Zhang,Hao Wu,Zhiyue Zhang
Immunotherapy has fundamentally altered cancer treatment; however, its effectiveness is clinically hampered by insufficient intratumoral T lymphocyte infiltration and failed T lymphocyte priming. Additionally, inducing cancer-specific immune responses while sparing normal cells remains challenging. Herein, we developed a redox-activatable polymeric nanoswitch (c-N@IM/JQ) that remained ‘off’ status in circulation but rapidly switched ‘on' after entering the tumor. Toll-like receptor (TLR) 7/8 agonist (imidazoquinoline, IMQ) and bromodomain and extraterminal inhibitor (JQ1) are locked in c-N@IM/JQ with a redox-cleavable linker (switch off). Upon systemic administration , c-N@IM/JQ with c-RGD peptide modification preferentially accumulated at tumor sites and responded to the high glutathione levels to release native IMQ for fully mobilizing T lymphocyte army, and JQ1 for removing the programmed death ligand (PD-L)-1 protection on tumor cells (switch on). These strengthened T lymphocyte armies are easily accessible to these de-protected tumor cells, revitalizing the immune response against tumors.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）