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PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

Yumeng Wang, Guiling Li

《医学前沿（英文）》 2019年 第13卷 第4期   页码 438-450 doi: 10.1007/s11684-018-0674-4

摘要： Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-1/PD-L1-related therapeutic strategies for CC.

关键词： PD-1     PD-L1     immune checkpoint blockade antibody     immunotherapy     cervical cancer    

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Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms

《医学前沿（英文）》   页码 805-822 doi: 10.1007/s11684-023-1025-7

摘要： Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

关键词： CTLA-4     PD-1     PD-L1     immune checkpoint blockade (ICB)     metabolic reprogramming     combined tumor therapeutic strategies    

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Activation of phagocytosis by immune checkpoint blockade

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 473-480 doi: 10.1007/s11684-018-0657-5

摘要：

Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-α (SIRPα), on tumor-associated macrophages (TAMs) and its cognate ligand cluster of differentiation 47 (CD47) on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 (PD-1) in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.

关键词： CD47     PD-1     PD-L1     immunotherapy     TAM     phagocytosis     macrophage    

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Molecular classification and precision therapy of cancer: immune checkpoint inhibitors

null

《医学前沿（英文）》 2018年 第12卷 第2期   页码 229-235 doi: 10.1007/s11684-017-0581-0

摘要：

On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as “genetic interpreters” or “genetic translators” and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.

关键词： molecular classification     precision medicine     pembrolizumab     PD-1/PD-L1     MSI-H    

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Application of StrucGP in medical immunology: site-specific -glycoproteomic analysis of macrophages

《医学前沿（英文）》 2023年 第17卷 第2期   页码 304-316 doi: 10.1007/s11684-022-0964-8

摘要： The structure of N-glycans on specific proteins can regulate innate and adaptive immunity via sensing environmental signals. Meanwhile, the structural diversity of N-glycans poses analytical challenges that limit the exploration of specific glycosylation functions. In this work, we used THP-1-derived macrophages as examples to show the vast potential of a N-glycan structural interpretation tool StrucGP in N-glycoproteomic analysis. The intact glycopeptides of macrophages were enriched and analyzed using mass spectrometry (MS)-based glycoproteomic approaches, followed by the large-scale mapping of site-specific glycan structures via StrucGP. Results revealed that bisected GlcNAc, core fucosylated, and sialylated glycans (e.g., HexNAc4Hex5Fuc1Neu5Ac1, N4H5F1S1) were increased in M1 and M2 macrophages, especially in the latter. The findings indicated that these structures may be closely related to macrophage polarization. In addition, a high level of glycosylated PD-L1 was observed in M1 macrophages, and the LacNAc moiety was detected at Asn-192 and Asn-200 of PD-L1, and Asn-200 contained Lewis epitopes. The precision structural interpretation of site-specific glycans and subsequent intervention of target glycoproteins and related glycosyltransferases are of great value for the development of new diagnostic and therapeutic approaches for different diseases.

关键词： macrophage     glycoproteome     glycopeptides     N-glycan structures     PD-L1    

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基于表位定向细胞库筛选高亲和力PD-1突变体诱骗分子 Article

刘昊, 乔春霞, 胡乃静, 王志宏, 王晶, 冯健男, 沈倍奋, 马远方, 罗龙龙

《工程（英文）》 2021年 第7卷 第11期   页码 1557-1565 doi: 10.1016/j.eng.2020.11.011

摘要： PD-1/PD-L1信号通路在肿瘤微环境中可抑制T细胞活化，使其成为一个热门的抗癌靶点。野生型（wild type, WT）PD-1胞外结构域由于亲和力低而难以阻断PD-1/PD-L1复合物的形成。本文利用三维（3D）晶体复合结构分析了PD-1与PD-L1或PD-L2的相互作用。文中还报道了PD-1与其临床抗体Opdivo结合模式的理论研究。通过对PD-1及其配体（即PD-L1和PD-L2）或抗体Opdivo的理论结合分析，建立了PD-1的一个小库容量、表位定向的哺乳动物细胞文库。经过三轮细胞分选，筛选出对PD-L1有较高亲和力的PD-1突变体463（亲和力较野生型PD-1提高近3个数量级）。它对PD-1具有抑制作用，可阻止PD-1与PD-L1形成复合物，这与商品化的抗PD-L1抗体atezolizumab（ATE）的作用相似。

关键词： 诱饵程序性细胞死亡蛋白-1     程序性细胞死亡配体-1     哺乳动物细胞文库     表位定向    

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Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian

《医学前沿（英文）》 2019年 第13卷 第1期   页码 32-44 doi: 10.1007/s11684-018-0678-0

摘要：

Immunotherapy has become the fourth cancer therapy after surgery, chemotherapy, and radiotherapy. In particular, immune checkpoint inhibitors are proved to be unprecedentedly in increasing the overall survival rates of patients with refractory cancers, such as advanced melanoma, non-small cell lung cancer, and renal cell carcinoma. However, inhibitor therapies are only effective in a small proportion of patients with problems, such as side effects and high costs. Therefore, doctors urgently need reliable predictive biomarkers for checkpoint inhibitor therapies to choose the optimal therapies. Here, we review the biomarkers that can serve as potential predictors of the outcomes of immune checkpoint inhibitor treatment, including tumor-specific profiles and tumor microenvironment evaluation and other factors.

关键词： immune checkpoint     companion diagnosis     PD-L1     tumor mutation burden     immune score    

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

《医学前沿（英文）》 2021年 第15卷 第2期   页码 221-231 doi: 10.1007/s11684-020-0812-7

摘要： The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

关键词： mTOR     cancer therapy     resistance     GSK3     protein degradation     E3 ubiquitin ligase     PD-L1    

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Selective hydrogenation of acetylene over Pd/CeO

L. Jang

《化学科学与工程前沿（英文）》 2020年 第14卷 第6期   页码 929-936 doi: 10.1007/s11705-019-1912-2

摘要： Five hundred ppm Pd/CeO catalyst was prepared and evaluated in selective hydrogenation of acetylene in large excess of ethylene since ceria has been recently found to be a reasonable stand-alone catalyst for this reaction. Pd/CeO catalyst could be activated by the feed gas during reactions and the catalyst without reduction showed much better ethylene selectivity than the reduced one in the high temperature range due to the formation of oxygen vacancies by reduction. Excellent ethylene selectivity of ~100% was obtained in the whole reaction temperature range of 50°C–200°C for samples calcined at temperatures of 600°C and 800°C. This could be ascribed to the formation of Pd Ce O or Pd-O-Ce surface species based on the X-ray diffraction and X-ray photoelectron spectroscopy results, indicating the strong interaction between palladium and ceria.

关键词： selective hydrogenation     acetylene     Pd/CeO2     strong interaction    

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Dihydroartemisinin increased the abundance of by YAP1 depression that sensitizes hepatocellular carcinomato anti-PD-1 immunotherapy

《医学前沿（英文）》 2023年 第17卷 第4期   页码 729-746 doi: 10.1007/s11684-022-0978-2

摘要： The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

关键词： hepatocellular carcinoma     YAP1     Akkermansia muciniphila     anti-PD-1     dihydroartemisinin     bile acid    

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A perspective on the promoting effect of Ir and Au on Pd toward the ethanol oxidation reaction in alkaline

WEI, L. X. LUO, F. LI, J. L. ZHANG

《能源前沿（英文）》 2018年 第12卷 第4期   页码 501-508 doi: 10.1007/s11708-018-0586-7

摘要： There remain great challenges in developing highly efficient electrocatalysts with both high activity and good stability for the ethanol oxidation reaction in alkaline media. Herein, two architectures of tri-metallic PdIrAu/C electrocatalysts are designed and the promoting effect of Au and Ir on Pd toward the ethanol oxidation reaction (EOR) in alkaline media is investigated in detail. On the one hand, the tri-metallic Pd Au Ir/C electrocatalyst with a solid solution alloy architecture is less active relative to Pd Ir/C and Pd/C while the stabilizing effect of Au leads to both a higher activity and a lower degradation percentage after 3000 cycles of the accelerated degradation test (ADT) on Pd Au Ir/C than those on Pd Ir/C. On the other hand, the tri-metallic Pd Ir@(1/3Au)/C electrocatalyst with a near surface alloy architecture delivers a much higher activity with an improvement up to 50.4% compared to Pd Ir/C. It is speculated that for the tri-metallic Pd Ir@(1/3Au)/C electrocatalyst, certain Au atoms are well designed on surfaces to introduce an electronic modification, thus leading to an anti-poisoning effect and improving the EOR activity.

关键词： fuel cells     catalysts     ethanol oxidation     alkaline media     solid solution alloy     near surface alloy    

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Molecular dynamics simulations of initial Pd and PdO nanocluster growth in a magnetron gas aggregation

Pascal Brault, William Chamorro-Coral, Sotheara Chuon, Amaël Caillard, Jean-Marc Bauchire, Stève Baranton

《化学科学与工程前沿（英文）》 2019年 第13卷 第2期   页码 324-329 doi: 10.1007/s11705-019-1792-5

摘要： Molecular dynamics simulations are carried out for describing growth of Pd and PdO nanoclusters using the ReaxFF force field. The resulting nanocluster structures are successfully compared to those of nanoclusters experimentally grown in a gas aggregation source. The PdO structure is quasi-crystalline as revealed by high resolution transmission microscope analysis for experimental PdO nanoclusters. The role of the nanocluster temperature in the molecular dynamics simulated growth is highlighted.

关键词： molecular dynamics     cluster growth     plasma sputtering     nanocatalyst    

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Investigation of the preparation methodologies of Pd-Cu single atom alloy catalysts for selective hydrogenation

-L. Jang

《化学科学与工程前沿（英文）》 2015年 第9卷 第4期   页码 442-449 doi: 10.1007/s11705-015-1547-x

摘要： Galvanic replacement, co-impregnation and sequential impregnation have been employed to prepare Pd-Cu bimetallic catalysts with less than 1 wt-% Cu and ca. 0.03 wt-% Pd for selective hydrogenation of acetylene in excess ethylene. High angle annular dark field-scanning transmission electron microscopy (HAADF-STEM) and H chemisorption results confirmed that Pd-Cu single-atom alloy structures were constructed in all three bimetallic catalysts. Catalytic tests indicated that when the conversion of acetylene was above 99%, the selectivity of ethylene of these three single atom alloy catalysts was still more than 73%. Furthermore, the single atom alloy catalyst prepared by sequential incipient wetness impregnation was found to have the best stability among the three procedures used.

关键词： H2 pulse chemisorption     palladium-copper bimetallic catalyst     single atom alloy     acetylene hydrogenation     HAADF-STEM    

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Preparation and investigation of Pd doped Cu catalysts for selective hydrogenation of acetylene

-L. Jang, Jong K. Keum, Karren More, Changjun Liu, Xiaoliang Yan

《化学科学与工程前沿（英文）》 2020年 第14卷 第4期   页码 522-533 doi: 10.1007/s11705-019-1822-3

摘要： A series of PdCu bimetallic catalysts with low Cu and Pd loadings and different Cu: Pd atomic ratios were prepared by conventionally sequential impregnation (CSI) and modified sequential impregnation (MSI) of Cu and Pd for selective hydrogenation of acetylene. Characterization indicates that the supported copper (II) nitrate in the PdCu bimetallic catalysts prepared by MSI can be directly reduced to Cu metal particles due to the hydrogen spillover from Pd to Cu(NO ) crystals. In addition, for the catalysts prepared by MSI, Pd atoms can form PdCu alloy on the surface of metal particles, however, for the catalysts prepared by CSI, Pd tends to migrate and exist below the surface layer of Cu. Reaction results indicate that compared with CSI, the MSI method enables samples to possess preferable stability as well as comparable reaction activity. This should be due to the MSI method in favor of the formation of PdCu alloy on the surface of metal particles. Moreover, even Pd loading is super low,<0.045 wt-% in this study, by through adjusting Cu loading to an appropriate value, attractive reactivity and selectivity still can be achieved.

关键词： copper     palladium     catalysts     acetylene     selective hydrogenation    

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Synthesis, physicochemical characterizations and catalytic performance of Pd/carbon-zeolite and Pd/carbon-CeO

Zeinab JAMALZADEH, Mohammad HAGHIGHI, Nazli ASGARI

《环境科学与工程前沿（英文）》 2013年 第7卷 第3期   页码 365-381 doi: 10.1007/s11783-013-0520-5

摘要： In this work, xylene removal from waste gas streams was investigated via catalytic oxidation over Pd/carbon-zeolite and Pd/carbon-CeO nanocatalysts. Activated carbon was obtained from pine cone chemically activated using ZnCl and modified by H PO . Natural zeolite of clinoptilolite was modified by acid treatment with HCl, while nano-ceria was synthesized via redox method. Mixed supports of carbon-zeolite and carbon-ceria were prepared and palladium was dispersed over them via impregnation method. The prepared samples were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), Brunauer-Emmett-Teller surface area (BET), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric (TG) techniques. Characterization of nanocatalysts revealed a good morphology with an average particle size in a nano range, and confirmed the formation of nano-ceria with an average crystallite size below 60 nm. BET analysis indicated a considerable surface area for catalysts (~1000 m ·g ). FTIR patterns demonstrated that the surface groups of synthesized catalysts are in good agreement with the patterns of materials applied in catalyst synthesis. The performance of catalysts was assessed in a low-pressure catalytic oxidation pilot in the temperature range of 100°C–250°C. According to the reaction data, the synthesized catalysts have been shown to be so advantageous in the removal of volatile organic compounds (VOCs), representing high catalytic performance of 98% for the abatement of xylene at 250°C. Furthermore, a reaction network is proposed for catalytic oxidation of xylene over nanocatalysts.

关键词： Pd/carbon-CeO2     Pd/carbon-zeolite     pine cone     ZnCl2     catalytic oxidation     xylene    

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标题 作者 时间 类型 操作

PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives

Yumeng Wang, Guiling Li

期刊论文

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms

期刊论文

Activation of phagocytosis by immune checkpoint blockade

null

期刊论文

Molecular classification and precision therapy of cancer: immune checkpoint inhibitors

null

期刊论文

Application of StrucGP in medical immunology: site-specific -glycoproteomic analysis of macrophages

期刊论文

基于表位定向细胞库筛选高亲和力PD-1突变体诱骗分子

刘昊, 乔春霞, 胡乃静, 王志宏, 王晶, 冯健男, 沈倍奋, 马远方, 罗龙龙

期刊论文

Monitoring checkpoint inhibitors: predictive biomarkers in immunotherapy

Min Zhang, Jingwen Yang, Wenjing Hua, Zhong Li, Zenghui Xu, Qijun Qian

期刊论文

mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

期刊论文

Selective hydrogenation of acetylene over Pd/CeO

L. Jang

期刊论文

Dihydroartemisinin increased the abundance of by YAP1 depression that sensitizes hepatocellular carcinomato anti-PD-1 immunotherapy

期刊论文

A perspective on the promoting effect of Ir and Au on Pd toward the ethanol oxidation reaction in alkaline

WEI, L. X. LUO, F. LI, J. L. ZHANG

期刊论文

Molecular dynamics simulations of initial Pd and PdO nanocluster growth in a magnetron gas aggregation

Pascal Brault, William Chamorro-Coral, Sotheara Chuon, Amaël Caillard, Jean-Marc Bauchire, Stève Baranton

期刊论文

Investigation of the preparation methodologies of Pd-Cu single atom alloy catalysts for selective hydrogenation

-L. Jang

期刊论文

Preparation and investigation of Pd doped Cu catalysts for selective hydrogenation of acetylene

-L. Jang, Jong K. Keum, Karren More, Changjun Liu, Xiaoliang Yan

期刊论文

Synthesis, physicochemical characterizations and catalytic performance of Pd/carbon-zeolite and Pd/carbon-CeO

Zeinab JAMALZADEH, Mohammad HAGHIGHI, Nazli ASGARI

期刊论文