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The roles of exosomal immune checkpoint proteins in tumors

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Military Medical Research 2022年第3期9卷 365-375页

作者： Cheng Xing Heng Li Rui-Juan Li Le Yin Hui-Fang Zhang Zi-Neng Huang Zhao Cheng Ji Li Zhi-Hua Wang Hong-Ling Peng Department of Hematology The Second Xiangya HospitalCentral South UniversityChangsha410011China Institute of Molecular Hematology Central South UniversityChangsha410011China Hunan Key Laboratory of Tumor Models and Individualized Medicine Changsha410011China

Targeting immune checkpoints has achieved great therapeutic effects in the treatment of early-stage ***,most patients develop adaptive resistance to this *** latest evidence demonstrates that tumorderived exosomes may play a key role in systemic immune suppression and tumor *** this article,we highlight the role of exosomal immune checkpoint proteins in tumor immunity,with an emphasis on programmed death ligand 1(PD-L1) and cytotoxic T lymphocyte-associated antigen 4(CTLA-4),as well as emerging evidence on roles of T cell immunoglobulin-3(TIM-3),arginase 1(ARG1),and estrogen receptor binding fragment-associated antigen 9(EBAG9) expressed by exosomes.

关键词： Exosomes Tumor immune checkpoints

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2845-2858页

作者： Fangfang Lai Ming Ji Lei Huang Yunchen Wang Nina Xue Tingting Du Kai Dong Xiaoqing Yao Jing Jin Zhiqiang Feng Xiaoguang Chen Department of Pharmacology State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Pharmacochemistry Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Tianjin Chase Sun Pharmaceutical Co. Ltd.Tianjin 300170China

PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding ***,most PD-1/PD-L1 agents are administered intravenously,which may be uncomfortable for some cancer ***,we develop a novel oral-delivered small molecular,YPD-29B,which specifically targets human *** data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1,but did not inhibit any other immune ***,YPD-29B induced human PD-L1 dimerization and internalization,which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in ***-29B was modified as the YPD-30 prodrug to improve *** humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells,we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in *** together,our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.

关键词： PD-L1 Small molecular inhibitor Prodrug immune checkpoints Cancer immunotherapy

Identification of senescence-related molecular subtypes and key genes for prostate cancer

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Asian Journal of Andrology 2023年第2期25卷 223-229页

作者： De-Chao Feng Wei-Zhen Zhu Xu Shi Qiao Xiong Jia You Qiang Wei Lu Yang Department of Urology Institute of UrologyWest China HospitalSichuan UniversityChengdu 610041China

We identified distinct senescence-related molecular subtypes and critical genes among prostate cancer(PCa)patients undergoing radical prostatectomy(RP)or radical radiotherapy(RT).We conducted all analyses using R software and its suitable *** genes,namely,secreted frizzled-related protein 4(SFRP4),DNA topoisomerase II alpha(TOP2A),pleiotrophin(PTN),family with sequence similarity 107 member A(FAM107A),C-X-C motif chemokine ligand 14(CXCL14),prostate androgen-regulated mucin-like protein 1(PARM1),leucine zipper protein 2(LUZP2),cluster of differentiation 38(CD38),cartilage oligomeric matrix protein(COMP),vestigial-like family member 3(VGLL3),apolipoprotein E(APOE),and aldehyde dehydrogenase 2 family member(ALDH2),were eventually used to subtype PCa patients from The Cancer Genome Atlas(TCGA)database and GSE116918,and the molecular subtypes showed good correlations with clinical *** terms of the tumor immune environment(TME)analysis,compared with cluster 1,cancer-associated fibroblasts(CAFs)scored significantly higher,while endothelial cells scored lower in cluster 2 in TCGA *** was a statistically significant correlation between both CAFs and endothelial cells with biochemical recurrence(BCR)-free survival for PCa patients undergoing *** the GSE116918 database,cluster 2 had significantly lower levels of CAFs and tumor purity and higher levels of stromal,immune,and Estimation of STromal and immune cells in MAlignant Tumor tissues using Expression data(ESTIMATE)scores than cluster 1;in addition,patients with high levels of CAFs,stromal scores,immune scores,and ESTIMATE scores and low levels of tumor purity tended to suffer from *** on the median of differentially expressed checkpoints,high expression of CD96,hepatitis A virus cellular receptor 2(HAVCR2),and neuropilin 1(NRP1)in GSE116918 and high expression of CD160 and tumor necrosis factor(ligand)superfamily member 18(TNFSF18)in TCGA database were associated with a significantl

关键词： cellular senescence immune checkpoints molecular subtypes prostate cancer tumor immune environment

Recent advancements in the B7/CD28 immune checkpoint families:new biology and clinical therapeutic strategies

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Cellular & Molecular Immunology 2023年第7期20卷 694-713页

作者： Marc C.Pulanco Anne T.Madsen Ankit Tanwar Devin T.Corrigan Xingxing Zang Department of Microbiology and Immunology Albert Einstein College of MedicineNew YorkNY10461USA Department of Urology Albert Einstein College of MedicineNew YorkNY10461USA Department of Oncology Albert Einstein College of MedicineNew YorkNY10461USA Department of Medicine Albert Einstein College of MedicineNew YorkNY10461USA

The B7/CD28 families of immune checkpoints play vital roles in negatively or positively regulating immune cells in homeostasis and various *** basic and clinical studies have revealed novel biology of the B7/CD28 families and new therapeutics for cancer *** this review,we discuss the newly discovered KIR3DL3/TMIGD2/HHLA2 pathways,PD-1/PD-L1 and B7-H3 as metabolic regulators,the glycobiology of PD-1/PD-L1,B7x(B7-H4)and B7-H3,and the recently characterized PD-L1/B7-1 *** also cover the tumor-intrinsic and-extrinsic resistance mechanisms to current anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies in clinical ***,we review new immunotherapies targeting B7-H3,B7x,PD-1/PD-L1,and CTLA-4 in current clinical trials.

关键词： B7 family immune checkpoints metabolic regulators glycobiology therapy resistance

Small-molecule agents for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 905-952页

作者： Fang Wang Kai Fu Yujue Wang Can Pan Xueping Wang Zeyu Liu Chuan Yang Ying Zheng Xiaopeng Li Yu Lu Kenneth Kin Wah To Chenglai Xia Jianye Zhang Zhi Shi Zeping Hu Min Huang Liwu Fu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060China School of Pharmaceutical Sciences Tsinghua-Peking Center for Life SciencesBeijing Frontier Research Center for Biological StructureTsinghua UniversityBeijing 100084China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Cell Biology&Institute of Biomedicine National Engineering Research Center of Genetic MedicineMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou 511436China School of Pharmacy The Chinese University of Hong KongHong Kong 999077China Affiliated Foshan Maternity and Child Healthcare Hospital Southern Medical UniversityFoshan 528000China

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer *** induce long-term tumor regression and overall survival benefit in many types of *** the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for *** molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively *** of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor ***,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

关键词： Cancer immunotherapy Small-molecule agents immune checkpoints Oncogenic signaling Metabolic pathways Cytokine/chemokine signaling Antitumor immunity Tumor immune microenvironment

Multi-target combinatory strategy to overcome tumor immune escape

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Frontiers of Medicine 2022年第2期16卷 208-215页

作者： Yingyan Yu Department of General Surgery of Ruijin Hospital Shanghai Institute of Digestive Surgeryand Shanghai Key Laboratory for Gastric NeoplasmsShanghai Jiao Tong University School of MedicineShanghai 200025China

immune therapy has become the fourth approach after surgery,chemotherapy,and radiotherapy in cancer *** immune checkpoints were identified in the last decade since ipilimumab,which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4,had been approved by the US Food and Drug Administration(FDA)for the treatment of unresectable or metastatic melanoma in *** use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the ***,fewer people are benefitting from immune checkpoint inhibitor treatment in solid *** 80%of patients do not respond appropriately because of primary or acquired therapeutic *** with the characterization of more immune checkpoints,the combinatory treatment of multi-immune checkpoint inhibitors becomes a new option when monotherapy could not receive a good *** this work,the author focuses on the combination therapy of multiple immune checkpoints(does not include targeted therapy of oncogenes or chemotherapy),introduces the current progression of multiple immune checkpoints and their related inhibitors,and discusses the advantages of combination therapy,as well as the risk of immune-related adverse events.

关键词： immune checkpoints multi-target immune escape immune-related adverse events combination therapy

Functional crosstalk and regulation of natural killer cells in tumor microenvironment: Significance and potential therapeutic strategies

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Genes & Diseases 2023年第3期10卷 990-1004页

作者： Liping Wang Zhe Chen Guohong Liu Yunbao Pan Department of Laboratory Medicine Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei 430071China Department of Otolaryngology Head and Neck Surgery Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei 430071China Department of Radiology Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhanHubei 430071China

Natural killer (NK) cells eliminate a large variety of tumor cells and abnormal cells. However, NK cells in the tumor microenvironment (TME) are often functionally depleted. A few subsets of NK cells even promote tumor growth. This study reviewed the biological properties of NK cells, the dynamic phenotypic changes of NK cells in the TME, and the communication between NK cells and other immune and nonimmune cells.

关键词： Cellular communication immune checkpoints Immunotherapy Natural killer cells Tumor microenvir onment

Immunomodulatory Function of Pien Tze Huang in T Cell-Mediated Anti-tumor Activity against B16-F10,MC38 and Hep1-6 Tumor Models

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Chinese Journal of Integrative Medicine 2024年第4期30卷 348-358页

作者： FU Yu-bing LIU Chen-feng WANG Jin-jia JI Xiao-lin TANG Rong-han LIAO Kun-yu CHEN Ling-yue HONG Ya-zhen FAN Bin-bin WANG Shi-cong LIU Wen-Hsien State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life ScienceXiamen UniversityXiamenFujian Province(361102)China Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development ZhangzhouFujian Province(363000)China

Objective To investigate the anti-tumor effects of Pien Tze Huang(PZH)in mouse models of B16–F10 melanoma,MC38 colorectal cancer,Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma *** Various tumor models,including B16–F10,MC38 and Hep1-6 tumor hypodermic inoculation models,B16–F10 and Hep1-6 pulmonary metastasis models,Hep1-6 orthotopic implantation model,and chemically induced hepatocellular carcinoma model,were utilized to evaluate the anti-tumor function of *** growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 *** cell proliferation and death of tumor cells in vitro,as well as T cell activation markers,cytokine production and immune checkpoints analysis,single-cell suspensions were prepared from mouse spleen,lymph nodes,and tumors after PZH *** PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth(P0.05).Nevertheless,PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma,tumor necrosis factor alpha,and interleukin 2 in CD4^(+)T cells in vitro(P<0.01 or P<0.05).Importantly,PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8^(+)T cells(P<0.01 or P<0.05).Conclusion This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity,indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.

关键词： Pien Tze Huang metastasis anti-tumor immunity T cell activation T cell exhaustion immune checkpoints Chinese medicine

Prognostic Role and Potential Mechanisms of N6-methyladenosine-related Long Noncoding RNAs in Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2022年第2期10卷 308-320页

作者： Tianxing Dai Jing Li Linsen Ye Haoyuan Yu Mingbin Deng Wei Liu Hua Li Yang Yang Guoying Wang Department of Hepatic Surgery and Liver Transplant Program The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouGuangdongChina Department of Infectious Diseases and Hepatology Unit Nanfang HospitalSouthern Medi-cal UniversityGuangzhouGuangdongChina Guangdong Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhouGuangdongChina

Background and Aims:Numerous studies have explored the important role of N6-methyladenosine(m^(6)A)in ***,the interaction between m^(6)A and long noncoding RNAs(lncRNAs)is poorly ***,we systematically analyzed the role and prognostic value of m^(6)A-related lncRNAs in hepatocellular carcinoma(HCC).Methods:The m^(6)A-related lncRNAs were identified based on the correlation coefficients with m^(6)A-related genes in HCC from The Cancer Genome ***,a novel risk score model was determined using the least absolute shrinkage and selection operator Cox regression *** and multivariate Cox analyses were used to identify independent prog-nostic factors for overall survival(OS)of HCC;thereafter,a prognostic nomogram was ***:A total of 259 lncRNAs showed significant correlations with m^(6)A in HCC,while 29 lncRNAs had prognostic ***,six critical m^(6)A-related lncRNAs(NRAV,SNHG3,KDM4A-AS1,AC074117.1,AC025176.1,and AL031985.3)were screened out to construct a novel risk score model which classified HCC patients into high-and low-risk *** analy-ses revealed that patients in the high-risk group exhibited worse OS,both in the training and validation *** risk score was also identified as an independent prognostic factor of OS,and a nomogram was established and verified with superior prediction ***,the risk score signifi-cantly correlated with the expression of immune checkpoint genes and immune ***:These findings indicated the significant role of m^(6)A-related lncRNAs in HCC and the potential application of the novel risk score model for prognostic prediction.

关键词： Hepatocellular carcinoma N6-methyladenosine Long noncoding RNAs Prognosis immune checkpoints