Advanced Science
·
2025
·
IF 14.1
Xinyi Lu,Pingping Jin,Qianyun Tang,Min Zhou,Hanjie Xu,Chen Su,Lei Wang,Feng Xu,Min Zhao,Yongxiang Yin,Jinqiu Zhang,Zhen Jia,Xinrui Peng,Jie Zhou,Lu Wang,Yan Chen,Min Wang,Min Yang,Daozhen Chen,Yu Chen
Cervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD + ) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT CANCER DRUG TARGETS
·
2024
·Vol. 25
·期 3
·294-305
·
IF 2.3
Yiping Zheng,Jianfeng Cai,Qiuhong Ji,Luanmei Liu,Kaijun Liao,Lie Dong,Jie Gao,Yinghui Huang
BackgroundLung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer progression.MethodsEmploying in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-γ secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and PD-L1.ResultsLung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-γ secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell proliferation.ConclusionThis study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.
研究领域:
肿瘤学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 5
·1482
·
IF 4.927
Yacong An,Xundou Li,Fengjiao Yao,Jinhong Duan,Xian-Da Yang
The PD-1/PD-L1 pathway blockade can generate a good clinical response by reducing immunosuppression and provoking durable antitumor immunity. In addition to antibodies, aptamers can also block the interaction between PD-1 and PD-L1. For the in vivo application, however, free aptamers are usually too small in size and quickly removed from blood via glomerular filtration. To avoid renal clearance of aptamer, we conjugated the PD-L1 aptamer to albumin to form a larger complex (BSA-Apt) and evaluated whether BSA-Apt would enhance the in vivo antitumor efficacy. The PD-L1 aptamer was thiol-modified and conjugated to the amino group of BSA via a SMCC linker. The average size of BSA-Apt was 11.65 nm, which was above the threshold for renal clearance. Functionally, BSA-Apt retained the capability of the PD-L1 aptamer to bind with PDL1-expressing tumor cells. Moreover, both the free aptamer and BSA-Apt augmented the PBMC-induced antitumor cytotoxicity in vitro. Furthermore, BSA-Apt generated a significantly stronger antitumor efficacy than the free PD-L1 aptamer in vivo without raising systemic toxicity. The results indicate that conjugating the PD-L1 aptamer to albumin may serve as a promising strategy to improve the in vivo functionality of the aptamer and that BSA-Apt may have application potential in cancer immunotherapy.Keywords:PD-L1;aptamer;albumin;BSA-Apt;cancer;immunotherapy
研究领域:
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Qiuyang Huang,Xiaoling Zang,Zhiwei Zhang,Hang Yu,Baoyan Ding,Zhuangzhuang Li,Simin Cheng,Xin Zhang,Mustafa R.K. Ali,Xue Qiu,Zhihua Lv
The discovery of new anti-cancer drugs targeting the PD-1/PD-L1 pathway has been a research hotspot in recent years. In this study, biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 to PD-1. We screened dozens of potential cancer related endogenous compounds. Surprisingly, cyclic adenosine monophosphate (cAMP) was found to have a direct inhibitory effect on the PD-1/PD-L1 binding with an in vitro IC 50 value of about 36.4 ± 9.3 μM determined by homogeneous time-resolved fluorescence (HTRF) assay. cAMP could recover the proliferation of Jurkat T cells co-cultured with DU-145 cells and may suppress PD-L1 expression of DU-145 cells. cAMP was demonstrated to bind and induce PD-L1 dimerization by FRET assay, and also predicted by MD simulations and molecular docking. The finding of cAMP as a potential inhibitor directly targeting the PD-1/PD-L1 interaction could advance our understanding of the activity of endogenous compounds regulating PD-L1.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2022
·Vol. 189
·期 5
·1-10
·
IF 6.408
Wei Jinxiu,Zhu Kai,Chen Zengwei,Yang Zhaoyan,Yang Kuo,Wang Zhuyuan,Zong Shenfei,Cui Yiping
Programed cell death ligand 1 (PD-L1) is a protein biomarker overexpressed on exosomes derived from tumor cells. It plays an important role in tumor diagnosis, screening, evaluation of therapeutic efficacy, and prognosis. In this study, a facile method is presented to detect PD-L1-overexpressing cancer exosomes with high specificity and sensitivity. First, gold nanospheres (GNSs) were attached to the bottom of an eight-well chambered slide by electrostatic adsorption, forming the detection substrate. Then, Cy5-labeled CD63 aptamers (i.e., the capture probes) were modified on the GNSs by Au–S bond. After adding samples containing target exosomes which were stained by membrane dyes DiI in advance, FAM-labeled PD-L1 aptamers (i.e., the immunoprobes) were added to recognize PD-L1 on the target exosomes. By triple-color fluorescence co-localization (TFC) of the Cy5, DiI, and FAM channels, highly sensitive and reliable detection of the PD-L1-overexpressing exosomes was achieved in the concentration range 7.78 × 10 1 to 7.78 × 10 4 particles/mL with a detection limit down to 6 particles/mL. The advantages of the proposed detection method include the following; first, the detection substrate is easy to prepare and convenient to clean. Second, the TFC strategy can completely exclude nonspecific reaction sites and thus significantly improves the accuracy. Such a facile and reliable detection method holds a great potential in exosome-based cancer theranostics. Graphical abstract In this paper, we proposed a triple-color fluorescence co-localization (TFC) strategy to significantly improve the reliability of exosome detection and the detection substrate is easy to prepare and convenient to clean. In addition, the LOD is down to 6 particles/mL, which is quite low compared with other detection methods
研究领域:
癌症生物学
·
纳米技术
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2022
·
IF 10.334
Qing Li,Meng-Sheng Deng,Ren-Tao Wang,Hao Luo,Yuan-Yuan Luo,Dong-Dong Zhang,Kui-Jun Chen,Xiao-Fu Cao,Guang-Ming Yang,Tie-Mei Zhao,Bo Xu,Cheng-Xiong Xu,Jian-Min Wang
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.
研究领域:
呼吸病学
·
免疫学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Chemistry
·
2024
·
IF 3.8
Zhenghua Zhang,Yang Tian,Wenjun Gao,Yubin Hu,Liangping Luo,Lichang Lei,Shasha Shen,Dan Han
Objectives: Immune checkpoint inhibitors (ICIs) have demonstrated potential in inhibiting the growth of malignant pleural mesothelioma (MPM), and their efficacy is associated with the expression of programmed death-ligand 1(PD-L1). This study evaluated a PD-L1-targeted nanoprobe for detecting PD-L1 expression in a nude mouse model of malignant pleural mesothelioma (MPM).Methods: A PD-L1-binding peptide (WL-12) was conjugated with superparamagnetic iron oxide nanoparticles (SPIONs) to create the nanoprobe WL-12@Fe₃O₄. The nanoprobe’s stability, biotoxicity, targeting ability, and in vivo magnetic resonance (MR) imaging effects were assessed and compared to non-targeted Fe₃O₄ nanoparticles. ΔT2 values and PD-L1 expression were measured in H226 and MSTO-211H tumor tissues over 4 weeks to analyze correlations.Results: The WL-12@Fe₃O₄ nanoprobe demonstrated uniform distribution and a spherical shape, with a larger size (43.82 nm) and lower surface potential (−9.34 ± 0.54 mV) compared to Fe₃O₄ (32.67 nm, −20.20 ± 0.88 mV, P < 0.05). The XPS and FT-IR analysis results indicate the successful coupling of WL-12 with Fe3O4. It was well dispersed in serum and saline and showed no cytotoxicity or organ damage in vivo. The probe selectively accumulated in PD-L1-expressing MPM cells, especially MSTO-211H, and exhibited significantly higher uptake in high PD-L1-expressing H460 cells (930.22 ± 11.75 ng/mL) compared to low PD-L1-expressing A549 cells (254.89 ± 17.33 ng/mL, P < 0.05). Tumor iron levels in the WL-12@Fe₃O₄ group were significantly elevated (141.02 ± 17.33 μg/g) compared to controls (36.43 ± 3.56 μg/g, P < 0.05), with no significant differences in other organs (P > 0.05). The T2 values of H226 and MSTO-211H tumors decreased after probe injection, with ΔT2 values significantly higher in the targeted group than the nontargeted group (P < 0.05). ΔT2 values increased over 4 weeks, correlating strongly with PD-L1 expression (P < 0.05).Conclusion: The PD-L1-targeted nanoprobe with MRI is a promising tool for noninvasive, real-time assessment of PD-L1 expression in MPM.
研究领域:
肿瘤学
·
医学影像学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2024
·Vol. 48
·期 16
·7300-7307
·
IF 2.7
Chunxiong Lu,Dandan Zhu,Peng Zhou,Kangxia Yu,Yaling Liu,Hongyong Wang,Hao Wu,Jun Wu,Guoqing Han,Pei Zou
Enormous success has been achieved in antitumor therapy with PD-1/PD-L1 inhibitors; however, less than 3 out of 10 patients show clinical benefits. An interesting phenomenon of patients who experienced durable clinical responses to PD-L1 blockade usually being the patients with high PD-L1 expression was noticed. Accordingly, the evaluation of PD-L1 is of great benefit to predict the immunotherapy response against PD-1/PD-L1. A small-molecule single photon emission computed tomography (SPECT) tracer [99mTc]Tc-SG2C-CBM containing a biphenyl moiety was designed and synthesized for the measurement of PD-L1 expression. The radiolabeling yield (RLY) and radiochemical purity (RCP) of [99mTc]Tc-SG2C-CBM were detected to be over 93% under the optimized labeling conditions. [99mTc]Tc-SG2C-CBM was discovered to be equipped with not only good stability but also suitable lipophilicity. In the cellular assays, [99mTc]Tc-SG2C-CBM showed moderate affinity to PD-L1 and 6.87-fold higher uptake in A375-hPD-L1 cells than in A375 cells. Then, the in vivo biodistribution results of the A375-hPD-L1 tumor-bearing mice showed that the radioactivity uptake in tumors was about 2.96 ± 0.76 and 2.31 ± 0.26 fold that in muscles and bones at 2 h post-injection, respectively. SPECT imaging was consistent with the biological distribution of [99mTc]Tc SG2C-CBM, with the uptake being mainly in the liver and less pronounced in tumors. The results of these studies indicate that [99mTc]Tc-SG2C-CBM may be a probe for imaging PD-L1 expression, but further research is needed.
研究领域:
医学影像学
·
肿瘤学
·
药物化学
✓ 已验证
DOI
高影响因子
JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY
·
2024
·
IF 1.5
Xu Xiang,Mao Yiyin,Zhou Peng,Wu Yujing,Liu Yaling,Wang Hongyong,Lu Chunxiong,Zou Pei
In this study, a 99m Tc-labeled small molecule imaging probe [ 99m Tc]Tc-PG3C-CBM for PD-L1 imaging was designed. It showed a radiochemical yield of > 97% and good in vitro stability. Uptake in A375-hPD-L1 cells (17.07 ± 1.40%) was 4.5 times higher than in A375 cells (3.81 ± 0.19%). The probe demonstrated moderate PD-L1 affinity (K D : 11.6 ± 2.57 nM; IC 50 : 59.2 ± 2.40 nM). Additionally, SPECT/CT imaging and biodistribution results indicated that [ 99m Tc]Tc-PG3C-CBM was mainly metabolized by the liver and showed some accumulation at the tumor site. These results suggest that [ 99m Tc]Tc-PG3C-CBM could potentially target PD-L1 at tumor sites.
研究领域:
核医学
·
分子影像学
·
肿瘤学
✓ 已验证
DOI
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2023
·Vol. 59
·期 3
·193-203
·
IF 2.1
Li Zhe,Jiang Da,Liu Fengling,Li Ying
Palmitoylation is a post-translational modification occurring on cysteine residues, which process is catalyzed by a family of zinc finger Asp-His-His-Cys (DHHC) domain-containing (ZDHHC) protein acyltransferases. As a family member, ZDHHC9 plays a crucial role in varied malignancies by regulating protein stability via protein substrate palmitoylation. Based on the bioinformatic analysis of GEO gene microarray GSE75037 (|log 2 fold change|> 1, P < 0.05), ZDHHC9 was defined as a significantly upregulated gene in lung adenocarcinoma (LUAD), which was also confirmed in our collected clinical specimens. It is necessary to explore the biological function of ZDHHC9 in LUAD cells. The follow-up functional experiments revealed that ZDHHC9 deficiency inhibited proliferation, migration, and invasion, while stimulated apoptosis in HCC827 cells. Besides, these malignant phenotypes could be accelerated by ZDHHC9 overexpression in A549. Moreover, we revealed that ZDHHC9 knockdown could promote PD-L1 protein degradation by reducing its palmitoylation level. The reduction of PD-L1 protein level could enhance anti-tumor immunity and inhibit the growth of LUAD cells. Therefore, our study uncovers the tumor-promoting role of ZDHHC9 in LUAD via regulating PD-L1 stability through palmitoylation, highlighting ZDHHC9 as a novel therapeutic target for LUAD. Graphical abstract
研究领域:
肿瘤学
·
分子生物学
·
癌症免疫学
✓ 已验证
DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2025
·
IF 10.5
Gang Bai,Zhichao Fan,Xiaoxin Zhao,Yan Dong,Congcong Tan,Liyuan Bai,Haoran Jiang,Taorui Liu,Jianjun Li,Xiang Zhao,Hua Yu
PD-L1 + exosomes act as a useful biomarker in early cancer diagnosis, therapeutic monitoring, prognostic assessment, and immunotherapy for non-invasive liquid biopsy. There exists urgent clinical need for developing rapid, portable, and cost-effective immediate assays for PD-L1 + exosomes. Here, we proposed a smartphone-assisted colorimetric sensor using the triple-helix molecular switch (THMS) combined with Y-shaped catalytic hairpin assembly (Y-CHA) reaction. Namely, this strategy initiates the Y-CHA cycle and forms Y-DNA G-quadruplex/Hemin DNAzyme with K + and Hemin after specific recognition of PD-L1 + exosomes by THMS. Then, PD-L1 + exosomes could be quantified via the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB)-mediated color change. The method demonstrates excellent specificity and sensitivity, with a limit of detection (LOD) of 5.45 × 10 3 particles/mL and an LOD of 8.56 × 10 3 particles/mL using smartphone analysis. With this strategy, we found that PD-L1 + exosome levels were significantly elevated in the peripheral blood of patients with colorectal cancer liver metastases (CRLM), indicating great potential for identifying CRLM patients. Additionally, this colorimetric sensor can be used to quantify PD-L1 + exosomes across wide range of cancers, which possess a great prospect in the point-of-care testing filed for cancer companion diagnosis.
研究领域:
医学诊断
·
分子生物学
·
生物传感技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Kai Guo,Hui Liu,Mengmeng Zhang,Nengyi Ni,Mengyao Mu,Ke Ren,Jiahui Chen,Qing Fan,Xueli Xu,Xiao Sun,Ximing Wang
Low-dose radiotherapy can lead to upregulation of PD-L1 expression in tumor cells, limiting the effectiveness of radio-immunotherapy. Currently, anti-PD-L1 drugs only disrupt the interaction of the PD-1/PD-L1 axis on the cell surface, without considering the immune regulatory ability of intracellular PD-L1. Additionally, antibody-bound PD-L1 can lead to internalization and recycling, allowing tumor cells to regain immune suppression. In this study, a novel PD-L1-affibody (Z PD-L1 )-grafted gadolinium-palladium nanoplatform incorporated with glucose oxidase (GOx) (GPGP) was fabricated to improve tumor-targeted magnetic resonance imaging (MRI) and synergistic radio-immunotherapy. GPGP with catalase- and peroxidase-like activity could catalyze the generation of oxygen to relieve tumor hypoxia and the generation of •OH to boost ferroptosis, respectively. GOx could enhance the nanoplatform’s dual nanozyme activity in a cascade, further sensitizing radiotherapy and intensifying subsequent immunogenic cell death. Crucially, GPGP induced AMPK phosphorylation and downregulated CMTM6, inhibiting intracellular PD-L1 production and blocking its transport to the cell membrane, thereby overcoming low-dose radiotherapy-induced PD-L1 upregulation. Systemic delivery of GPGP also demonstrated notable MRI contrast enhancement, providing precise imaging guidance for determining the optimal timing for radiotherapy. Therefore, GPGP has shown great potential in achieving effective MRI and collaborative tumor radio-immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
·
放射生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）