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Chinese Journal of Cancer Research 2023年第3期35卷 245-251页

作者： Cunte Chen Yangqiu Li Department of Hematology Guangzhou First People’s HospitalSchool of MedicineSouth China University of TechnologyGuangzhou 510180China Institute of Hematology School of MedicineKey Laboratory for Regenerative Medicine of Ministry of EducationJinan UniversityGuangzhou 510632China

Co-expression of immune checkpoint(IC)molecules can exacerbate T cell exhaustion in patients with hematological malignancies(HMs)and contribute to the immune escape of tumor cells,which is related to poor clinical *** is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical *** this perspective,we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs,providing new insights for designing dual IC blockades(ICBs).

关键词： immune checkpoint T cell exhaustion co-expression pattern prognosis hematological malignancy

A Prognostic Nomogram for Hepatocellular Carcinoma Based on Wound Healing and immune checkpoint Genes

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Journal of Clinical and Translational Hepatology 2022年第5期10卷 891-900页

作者： Beiyuan Hu Xiaotian Shen Wei Qin Lan Zhang Tiantian Zou Qiongzhu Dong Lun-Xiu Qin Department of General Surgery Huashan Hospital&Cancer Metastasis InstituteInstitutes of Biomedical SciencesFudan UniversityShanghaiChina

Background and Aims:Wound healing and tumor progression share some common biological features;however,how variations in wound healing patterns affect hepatocellular carcinoma(HCC)prognosis remains ***:We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas(TCGA)and the International Cancer Genome Consortium(ICGC)and correlated them with immune infiltration and the expression levels of immune checkpoint genes.A risk score,which we named the“***”score,was established via stepwise Cox *** constructed a nomogram based on age,sex,TNM stage,and *** score and explored its predictive value for HCC ***-four clinical patients were enrolled in this study,and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation ***:We identified two distinct wound healing patterns in *** biological processes of healing cluster 1(C1)are related to metabolism,while those of healing cluster 2(C2)are related to the inflammatory response and immune cell accumulation.A total of 565 wound healing-related genes(based on Gene Ontology)and 25 immune checkpoint genes were *** analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis,six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the“***”gene set(FCER1G,PLAT,ITGA5,CCNB1,CD86 and CD40).The“***”gene set,as an OS risk factor,was further validated in Fudan *** constructed a nomogram to predict the 1-,3-and 5-year overall survival(OS)in the TCGA *** area under curve vales of the receiver characteristic operator curves were 0.82,0.76 and 0.73 in the training group and 0.84,0.76 and 0.72 in the test ***:We established a prognostic nomogram based on the *** gene signature,which includes six wound healing-and immunity-related *** nomogram accurately predicts the OS of HCC

关键词： Hepatocellular carcinoma Bioinformatics immune checkpoint Wound healing Prognosis

Unveiling T cell evasion mechanisms to immune checkpoint inhibitors in acute myeloid leukemia

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Cancer Drug Resistance 2023年第3期6卷 674-687页

作者： Lindsay Gurska Kira Gritsman Department of Cell Biology Albert Einstein College of MedicineBronxNY 10461USA Department of Medical Oncology Montefiore Medical CenterAlbert Einstein College of MedicineBronxNY 10461USA

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy that is associated with a high relapse rate and poor prognosis. Despite advances in immunotherapies in solid tumors and other hematologic malignancies, AML has been particularly difficult to treat with immunotherapies, as their efficacy is limited by the ability of leukemic cells to evade T cell recognition. In this review, we discuss the common mechanisms of T cell evasion in AML: (1) increased expression of immune checkpoint molecules;(2) downregulation of antigen presentation molecules;(3) induction of T cell exhaustion;and (4) creation of an immunosuppressive environment through the increased frequency of regulatory T cells. We also review the clinical investigation of immune checkpoint inhibitors (ICIs) in AML. We discuss the limitations of ICIs, particularly in the context of T cell evasion mechanisms in AML, and we describe emerging strategies to overcome T cell evasion, including combination therapies. Finally, we provide an outlook on the future directions of immunotherapy research in AML, highlighting the need for a more comprehensive understanding of the complex interplay between AML cells and the immune system.

关键词： Acute myeloid leukemia T cells immune checkpoint immune evasion

LILRB4, an immune checkpoint on myeloid cells

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Blood Science 2022年第2期4卷 49-56页

作者： Ting Yang Yixin Qian Xiaoting Liang Jianbo Wu Ming Zou Mi Deng Peking University International Cancer Institute Health Science CenterPeking UniversityBeijingChina Peking University Cancer Hospital and Institute Peking UniversityBeijingChina

Leukocyte immunoglobulin-like receptor B4(LILRB4)is an inhibitory receptor in the LILR family mainly expressed on normal and malignant human cells of myeloid *** binding to ligands,LILRB4 is activated and subsequently recruits adaptors to cytoplasmic immunoreceptor tyrosine inhibitory motifs to initiate different signaling cascades,thus playing an important role in physiological and pathological conditions,including autoimmune diseases,microbial infections,and *** normal myeloid cells,LILRB4 regulates intrinsic cell activation and *** disease-associated or malignant myeloid cells,LILRB4 is significantly correlated with disease severity or patient survival and suppresses T cells,thereby participating in the pathogenesis of various *** summary,LILRB4 functions as an immune checkpoint on myeloid cells and may be a promising therapeutic target for various human immune diseases,especially for cancer immunotherapy.

关键词： Autoimmune disease Cancer immune checkpoint Immunotherapy Inhibitory receptor LILR LILRB4,MDSC Myeloid cell TAM

immune checkpoint:The novel target for antitumor therapy

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Genes & Diseases 2021年第1期8卷 25-37页

作者： Xianghu Jiang Guohong Liu Yirong Li Yunbao Pan Department of Laboratory Medicine Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei430072PR China Department of Radiology Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei430072PR China

Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during *** pathways are essential to down-regulate the immune system by blocking the activation of T *** recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall ***,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably ***,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint *** are two points in *** the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized *** the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).

关键词： Circulating tumor DNA(ctDNA) Cytotoxic Tlymphocyteassociated protein 4(CTLA-4) Exosome immune checkpoint Lymphocyteactivation gene 3(LAG-3) Programmed cell death protein ligand 1(PD-L1) Programmed death-1 receptor(PD-1) T cell immunoglobulin

Application of immune checkpoint targets in the anti-tumor novel drugs and traditional Chinese medicine development

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Acta Pharmaceutica Sinica B 2021年第10期11卷 2957-2972页

作者： Yuli Wang Xingyan Zhang Yuyan Wang Wenjing Zhao Huling Li Lixing Zhang Xinping Li Tiejun Zhang Hongbing Zhang He Huang Changxiao Liu Key Laboratory of Systems Bioengineering(Ministry of Education) School of Chemistry Engineering and TechnologyTianjin UniversityTianjin 300072China State Key Laboratory of Drug Delivery Technology and Pharmacokinetics Tianjin Institute of Pharmaceutical ResearchTianjin 300193 China Tianjin Key Laboratory of Quality-Marker of Traditional Chinese Medicines Tianjin Institute of Pharmaceutical ResearchTianjin 300193 China Tianjin University of Traditional Chinese Medicine Tianjin 300193 China The Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of Thoracic Medical OncologyBeijing Institute of Cancer ResearchBeijing 100142 China Department of Pharmacology Tianjin Medical UniversityTianjin 300070China MITRO Biotech Co. Ltd.Nanjing 211100China

immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance,preventing autoimmune responses,and minimizing tissue damage by regulating the duration and intensity of the immune ***,immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor *** on substantial physiological analyses as well as preclinical and clinical studies,checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of *** the last few years,extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines(TCMs).The main advantage of TCMs and natural medicine is that they usually contain multiple active components,which can act on multiple targets at the same time,resulting in additive or synergistic *** strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great *** example,Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals,and these antibodies can overcome the exhaustion of immune cells under tumor immune ***,many other TCM molecules could also be novel and effective drug candidates for the treatment of ***,it is essential to assess the application of immune checkpoints in the development of new drugs and *** this review,we focus on research progress in the field of immune checkpoints based on three topics:(1)immune checkpoint targets and pathways,(2)development of novel immune checkpoint-based drugs,and(3)application of immune checkpoints in the development of TCMs.

关键词： immune checkpoint Therapeutic target Signaling pathway Drug development Traditional Chinese medicine Immunoregulatory Cancer immunity

Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies

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Genes & Diseases 2019年第3期6卷 232-246页

作者： Hongxing Shen Eddy Shih-Hsin Yang Marty Conry John Fiveash Carlo Contreras James A.Bonner Lewis Zhichang Shi Department of Radiation Oncology The University of Alabama at Birmingham School of MedicineBirminghamAL35233USA O’Neal Comprehensive Cancer Center The University of Alabama at Birmingham School of MedicineBirminghamAL35233USA Department of Medical Oncology The University of Alabama at Birmingham School of MedicineBirminghamAL35233USA Department of Surgical Oncology The University of Alabama at Birmingham School of MedicineBirminghamAL35233USA Department of Microbiology The University of Alabama at Birmingham School of MedicineBirminghamAL35233USA Program in Immunology The University of Alabama at Birmingham School of MedicineBirminghamAL35233USA

immune checkpoint blockade therapies(ICBs)are a prominent breakthrough in cancer immunotherapy in recent years(named the 2013“Breakthrough of the Year”by the Science magazine).Thus far,FDA-approved ICBs primarily target immune checkpoints CTLA-4,PD-1,and *** their impressive long-term therapeutic benefits,their efficacy is limited to a small subset of cancer *** addition,ICBs induce inadvertent immune-related adverse events(irAEs)and can be costly for long-term *** overcome these limitations,two strategies are actively being pursued:identification of predictive biomarkers for clinical response to ICBs and multi-pronged combination *** will allow clinicians to practice a precision medicine approach in ICBs(biomarker-based patient selection)such as treating triple-negative breast cancer patients that exhibit PD-L1 staining of tumor-infiltrating immune cells in1%of the tumor area with nanoparticle albumin-bound(nab)epaclitaxel plus anti-PD-L1 and treating patients of MSI-H or MMR deficient unresectable or metastatic solid tumors with pembrolizumab(anti-PD-1).Importantly,the insights gained from these biomarker studies can guide rational combinatorial strategies such as CDK4/6 inhibitor/fractionated radiotherapy/HDACi in conjunction with ICBs to maximize therapeutic ***,with the rapid technological advents(e.g.,ATCT-Seq),we predict more reliable biomarkers will be identified,which in turn will inspire more promising combination therapies.

关键词： IFN-γ immune checkpoint Microbiota Microsatellite instability Neoantigen PD-L1 Radiotherapy

Pivotal role of long non-coding ribonucleic acid-X-inactive specific transcript in regulating immune checkpoint programmed death ligand 1 through a shared pathway between miR-194-5p and miR-155-5p in hepatocellular carcinoma

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World Journal of Hepatology 2020年第12期12卷 1211-1227页

作者： Sara M Atwa Heba Handoussa Karim M Hosny Margarete Odenthal Hend M El Tayebi Pharmaceutical Biology Department German University in CairoCairo 11865Egypt Department of General Surgery Faculty of MedicineCairo UniversityCairo 11562Egypt Institute for Pathology University Hospital CologneCologne 50924Germany Molecular Pharmacology Research Group Department of Pharmacology and ToxicologyFaculty of Pharmacy and BiotechnologyGerman University in CairoCairo 11835Egypt

BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the ***,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint ***-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic *** the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/***,nutraceutical therapeutics in cancers have received increasing ***,it is interesting to study the impact of oleuropein on the respective study key *** To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/*** Bioinformatics tools including *** and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,*** addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and *** and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 *** study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried *** Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and ***-1 and XIST were predicted to target PD-L1 ***-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely ***-194 induced expression elevated the expression of PD-L1,XIST and ***,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MA

关键词： Hepatocellular carcinoma X-inactive specific transcript MiR-155-5p MiR-194-5p Programmed cell-death protein 1/Programmed death ligand 1 immune checkpoint

immune checkpoint B7-H1 monoclonal antibodies for immunohistochemistry test in the diagnosis of colorectal cancer

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Immune checkpoint B7-H1 monoclonal antibodies for immunohist...

The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation

第十二届全国免疫学学术大会

作者： Huang Ziyi Cao Lei Gu Yanzheng Zhang Ningyan An Zhiqiang Zhang Xueguang The First Affiliated Hospital of Soochow University Jiangsu Key Laboratory of Clinical Immunology Soochow University Jiangsu Key Laboratory of Gastrointestinal tumor Immunology Texas Therapeutics Institute University of Texas Health Science Center at Houston

The finding that tumors could actively suppress immunity has led to the development of ’checkpoint blockades’ that prevent this *** of the recently discovered mechanisms was co-inhibitory molecules expressed by tumor cells,immune cells and stromal cells in the tumor microenvironment attenuated T cell responses against cancer *** group of co-inhibitory molecules is called immune checkpoint molecules including CTLA-4,PD-1,B7-H1(PD-L1),B7-H3 and *** therapies targeting the inhibitory checkpoint PD-1 have demonstrated promising activity in several cancers,among which some PD-L1 positive tumors demonstrated higher response rates to anti PD-1 therapies,suggesting that identifying PD-L1 expression could be a predictive biomarker to select patients likely to respond to anti PD-1 ***,we found that B7-H1 was highly expressed in colorectal cancer tissues and showed differential expression levels during disease progression.B7-H1 expression in colorectal cancer tissues can be heterogeneous in staining intensity and have variable distribution throughout an individual *** succeeded in developing anti-human B7-H1 and CD8 mAbs suitable for immunohistochemical staining in formalin-fixed tissue sections with reliable clarity and *** was applied to identify B7-H1 that correlated with colorectal cancer status,T cell infiltrate,and patient survival.B7-H1 expressed in the early stages of colorectal evolution was one of the earliest inhibitory molecules of the B7 family to be engaged in the development of colorectal cancer,which could be significant to determine the immune classification(immunoscore) in cancer *** mAbs are potentially useful as companion diagnostic agents to analyze B7-H1 expression in the clinical setting while the expression pattern in the corresponding stage will be important to clarify tumor immune escape mechanism at different stages of colorectal cancer.

关键词： immune checkpoint monoclonal antibodies colorectal cancer immunohistochemistry

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Cellular & Molecular Immunology 2018年第5期15卷 438-446页

作者： Wenwen Xu TạMinh Hiếu Subramaniam Malarkannan Li Wang Department of Microbiology and Immunology MilwaukeeWI 53226USA Department of Medicine MilwaukeeWI 53226USA Department of Pediatrics Medical College of WisconsinMilwaukeeWI 53226USA Blood Research Institute MilwaukeeWI 53226USA

Among various immunoregulatory molecules,the B7 family of immune-checkpoint receptors consists of highly valuable targets for cancer *** targeting two B7 family co-inhibitory receptors,CTLA-4 and PD-1,have elicited long-term clinical outcomes in previously refractory cancer types and are considered a breakthrough in cancer *** the success,the relatively low response rate(20–30%)warrants efforts to identify and overcome additional immune-suppressive *** the expanding list of T cell inhibitory regulators,V domain immunoglobulin suppressor of T cell activation(VISTA)is a unique B7 family checkpoint that regulates a broad spectrum of immune ***,we summarize recent advances that highlight the structure,expression,and multi-faceted immunomodulatory mechanisms of VISTA in the context of autoimmunity,inflammation,and anti-tumor immunity.

关键词： cancer immunotherapy immune checkpoint autoimmunity inflammation tumor immunity