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Targeting the chromatin structural changes of antitumor immunity

Journal of Pharmaceutical Analysis 2024年第4期14卷 460-482页

作者： Nian-nian Li Deng-xing Lun Ningning Gong Gang Meng Xin-ying Du He Wang Xiangxiang Bao Xin-yang Li Ji-wu Song Kewei Hu Lala Li Si-ying Li Wenbo Liu Wanping Zhu Yunlong Zhang Jikai Li Ting Yao Leming Mou Xiaoqing Han Furong Hao Yongcheng Hu Lin Liu Hongguang Zhu Yuyun Wu Bin Liu Weifang People's Hospital WeifangShandong261000China School of Life Sciences Nankai UniversityTianjin300071China Weifang Traditional Chinese Medicine Hospital WeifangShandong261000China Shaanxi Key Laboratory of Sericulture Ankang UniversityAnkangShaanxi725000China Guizhou Education University Guiyang550018China Guizhou Normal University Guiyang550025China School of Medical Imaging Weifang Medical UniversityWeifangShandong261053China Department of Bone and Soft Tissue Oncology Tianjin HospitalTianjin300299China Xinqiao Hospital of Army Military Medical University Chongqing400038China Teda Institute of Biological Sciences&Biotechnology Nankai UniversityTianjin300457China

Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of *** defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their ***,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research *** emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.

关键词： antitumor immunity Chromatin structural Cancer epigenetics DNA methylation Histone modification Chemotherapy

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antitumor immunity of human SART3 gene vaccine against mouse tumor in vitro/vivo

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Frontiers of Medicine 2008年第1期2卷 51-57页

作者： Yu HE Shuhua YANG Yong LIU Tao LI Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

To determine whether squamous cell carcin-oma antigen recognized by human T cell 3(SART3)gene can induce antitumor immunity against tumor cells which express the gene,we constructed mouse tumor cells expressing human SART3(LM8-SART3)and carried out experiments in vitro/*** subcutaneous injection with SART3 gene vaccine,cytotoxic T lymphocyte(CTL)activity in vitro was measured using Cell Counting *** for the in vivo part,C3H mice were divided into several *** group was challenged with tumor cells after *** group was treated with the vaccine after tumor *** was found that human SART3 DNA vaccine can elicit a specific CTL reaction from the mouse *** vaccination,tumor occurrence and tumor growth speed was *** vaccine also shows activity in tumor *** con-clude that the human SART3 DNA vaccine can induce antitumor ability against tumor cells expressing human SART3(LM8-SART3)in vitro/vivo which may provide new possibilities in antitumor therapy.

关键词： SART3 protein,human DNA vaccine antitumor immunity osteosarcoma

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Regulation of antitumor immunity by inflammation-induced epigenetic alterations

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Cellular & Molecular Immunology 2022年第1期19卷 59-66页

作者： Michael Karin Shabnam Shalapour Department of Pharmacology School of MedicineUniversity of California San DiegoLa JollaCAUSA Laboratory of Gene Regulation and Signal Transduction Department of PharmacologySchool of MedicineUniversity of California San DiegoLa JollaCAUSA Department of Cancer Biology University of Texas MD Anderson Cancer CenterHoustonTXUSA

Chronic inflammation promotes tumor development,progression,and metastatic dissemination and causes treatment *** accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor *** antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment *** inflammation,particularly acute inflammation,supports T-cell priming,activation,and infiltration into infected tissues,chronic inflammation is mostly ***,the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well *** data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor *** alterations can affect and modulate numerous aspects of cancer development,including tumor growth,the metabolic state,metastatic spread,immune escape,and immunosuppressive or immunosupportive leukocyte *** this review,we discuss the role of inflammation in initiating epigenetic alterations in immune cells,cancer-associated fibroblasts,and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.

关键词： Inflammation Epigenetics antitumor immunity Immunotherapy

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Dendritic Cell-Derived Exosomes Stimulate Stronger CD8^+ CTL Responses and antitumor immunity than TVimor Cell-Derived Exosomes

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Cellular & Molecular Immunology 2006年第3期3卷 205-211页

作者： Siguo Hao Ou Bai Jinying Yuan Mabood Qureshi Jim Xiang Research Unit Division of Health Research Saskatchewan Cancer Agency Departments of Oncology Immunology and Pathology College of Medicine University of Saskatchewan Saskatoon Saskatchewan STN 4H4 Canada Siguo Hao and Ou Bai made the same contribution in this study

Exosomes （EXO） derived from dendritic cells （DC） and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison of the stimulatory efficiency of the antitumor immune responses induced by these two commonly used EXO vaccines. In this study, we selected to study the phenotype characteristics of EXO derived from a transfected EG7 tumor cells expressing ovalbumin （OVA） and OVA-pulsed DC by flow cytometry. We compared the stimulatory effect in induction of OVA-specific immune responses between these two types of EXO. We found that OVA protein-pulsed DCOVA-derived EXO （EXODC） can more efficiently stimulate naive OVA-specific CD8^＋ T cell proliferation and differentiation into cytotoxic T lymphocytes in vivo, and induce more efficient antitumor immunity than EG7 tumor cell-derived EXO （EXOEG7）. In addition, we elucidated the important role of the host DC in EXO vaccines that the stimulatory effect of EXO is delivered to T cell responses by the host DC. Therefore, DC-derived EXO may represent a more effective EXO-based vaccine in induction of antitumor immunity. Cellular ＆ Molecular Immunology. 2006;3（3）：205-211.

关键词： dendritic cell exosome tumor cell cytotoxic T lymphocyte antitumor immunity

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CFTR is a negative regulator ofγδT cell IFN-γproduction and antitumor immunity

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Cellular & Molecular Immunology 2021年第8期18卷 1934-1944页

作者： Yuanyuan Duan Guangqiang Li Miaomiao Xu Xiaofei Qi Mingxia Deng Xuejia Lin Zhiwei Lei Yi Hu Zhenghu Jia Quanli Yang Guangchao Cao Zonghua Liu Qiong Wen Zhenhua Li Jie Tang Wei Kevin Zhang Pingbo Huang Limin Zheng Richard A.Flavell Jianlei Hao Zhinan Yin Zhuhai Precision Medical Center Zhuhai People’s Hospital(Zhuhai Hospital Affiliated with Jinan University)Jinan UniversityZhuhai519000GuangdongChina The Biomedical Translational Research Institute Faculty of Medical ScienceJinan UniversityGuangzhou510632GuangdongChina Department of Physiology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou510515GuangdongChina The First Affiliated Hospital Jinan UniversityGuangzhou510632China School of Pharmaceutical Sciences South-Central University for NationalitiesWuhan430074HubeiChina Division of Life Science Hong Kong University of Science and Technology(HKUST)Hong KongChina State Key Laboratory of Oncology in Southern China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou510060China Department of Immunobiology School of MedicineYale UniversityNew HavenCT06520USA

CFTR,a chloride channel and ion channel regulator studied mostly in epithelial cells,has been reported to participate in immune regulation and likely affect the risk of cancer ***,little is known about the effects of CFTR on the differentiation and function ofγδT *** this study,we observed that CFTR was functionally expressed on the cell surface ofγδT *** deletion and pharmacological inhibition of CFTR both increased IFN-γrelease by peripheralγδT cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in ***,the molecular mechanisms underlying the regulation ofγδT cell IFN-γproduction by CFTR were either TCR dependent or related to Ca^(2+)*** was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun *** addition,CFTR was found to modulate TCR-induced Ca^(2+)influx and membrane potential(Vm)-induced Ca^(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway inγδT ***,CFTR serves as a negative regulator of IFN-γproduction inγδT cells and the function of these cells in antitumor *** investigation suggests that modification of the CFTR activity ofγδT cells may be a potential immunotherapeutic strategy for cancer.

关键词： CFTR γδT cells TCR Membrane potential antitumor immunity

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LncRNA MEG3 promotes chemosensitivity of osteosarcoma by regulating antitumor immunity via miR-21-5p/p53 pathway and autophagy

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Genes & Diseases 2023年第2期10卷 531-541页

作者： Xin Huang Weiyue Zhang Feifei Pu Zhicai Zhang Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Endocrinology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

This study aimed to investigate the role of long non-coding RNA maternally expressed gene 3(lncRNA MEG3)in chemosensitivity of osteosarcoma(OS),and to reveal the possible underlying *** this study,we found that the expression of lncRNA MEG3 was significantly lower in OS tissues and cell ***,lncRNA MEG3 overexpression enhanced chemosensitivity of OS by inhibiting cell proliferation,migration,autophagy,and promoting antitumor *** MEG3 functioned as miR-21-5 sponge to regulate p53 expression in ***,lncRNA MEG3 promoted OS chemosensitivity by regulating antitumor immunity via miR-21-5p/p53 pathway and ***,this study provided the evidence that lncRNA MEG3 might be a promising therapeutic target for OS chemoresistance.

关键词： antitumor immunity Autophagy Chemosensitivity LncRNAMEG3 Osteosarcoma

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Interferon γ Stimulates Cellular Maturation of Dendritic Cell Line DC2.4 Leading to Induction of Efficient Cytotoxic T Cell Responses and antitumor immunity

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Cellular & Molecular Immunology 2007年第2期4卷 105-111页

作者： Tianpei He Chaoke Tang Shulin Xu Terence Moyana Jim Xiang Research Unit Health Research Division Saskatchewan Cancer Agency Departments of Oncology and Immunology University of Saskatchewan Saskatoon Saskatchewan S7N 4H4 Canada Department of Pathology and Laboratory Medicine University of Ottawa Ontario Canada

Dendritic cells （DCs） are the most potent antigen-presenting cells （APCs） for the initiation of antigen （Ag）-specific immune responses. In most studies, mature DCs are generated from bone marrow cells or peripheral monocytes; in either case, the harvested cells are then cultured in medium containing recombinant GM-CSF, IL-4 and TNF-α for 7-10 days and stimulated with lipopolysaccharide （LPS）. However, this approach is time-consuming and expensive. There is another less cost approach of using immobilized DC cell lines, which can easily grow in the medium. A disadvantage with the immobilized DC cell lines, however, is that they are immature DCs and lack expression of MHC class Ⅱ and costimulatory CD40 and CD80 molecules. This, therefore, limits their capacity for inducing efficient antitumor immunity. In the current study, we investigated the possible efficacy of various stimuli （IL-1β, IFN-γ, TNF-α CpG and LPS） in converting the immature dendritic cell line DC2.4 to mature DCs. Our findings were quite interesting since we demonstrated for the first time that IFN-γ was able to stimulate the maturation of DC2.4 cells. The IFN-γ-activated ovalbumin （OVA）-pulsed DC2.4 cells have capacity to upregulate MHC class Ⅱ, CD40, CD80 and CCR7, and to more efficiently stimulate in vitro and in vivo OVA-specific CD8^＋ T cell responses and antitumor immunity. Therefore, IFN-γ-activated immortal DC2.4 ceils may prove to be useful in the study of DC biology and antitumor immunity.

关键词： IFN-γ DC2.4 line DC maturation CTL antitumor immunity

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Myc inhibition tips the immune balance to promote antitumor immunity

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Cellular & Molecular Immunology 2022年第9期19卷 1030-1041页

作者： Chao Yang Yun Liu Yudi Hu Liang Fang Zhe Huang Huanhuan Cui Jun Xie Yazhen Hong Wei Chen Nengming Xiao Qiyuan Li Wen-Hsien Liu Changchun Xiao State Key Laboratory of Cellular Stress Biology School of Life SciencesFaculty of Medicine and Life SciencesXiamen UniversityXiamen361102FujianChina Institute of Hematology School of MedicineXiamen UniversityXiamen361102FujianChina Shenzhen Key Laboratory of Gene Regulation and Systems Biology School of Life Sciences and Academy for Advanced Interdisciplinary StudiesSouthern University of Science and TechnologyShenzhen518005GuangdongChina Sanofi Institute for Biomedical Research Suzhou215123JiangsuChina Department of Immunology and Microbiology The Scripps Research InstituteLa JollaCA92037USA

Aberrant expression of Myc is one of the most common oncogenic events in human *** of Myc inhibitors are currently under development for treating Myc-driven *** addition to directly targeting tumor cells,Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor ***,the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly ***,we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of *** genetic and pharmacologic approaches,we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T(Treg)cells and the differentiation of resting Treg(rTreg)cells to activated Treg(aTreg)cells in ***,we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of *** ablation of the Myc gene has been shown to suppress CD8 T cell function,Treg cells,which express much less Myc protein than CD8 T cells,are more sensitive to Myc *** differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc *** findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.

关键词： Myc inhibition Regulatory T cells Differential sensitivity antitumor immunity Cancer immunotherapy

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CD4^(+) T cell-released exosomes inhibit CD8^(+) cytotoxic T-lymphocyte responses and antitumor immunity

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Cellular & Molecular Immunology 2011年第1期8卷 23-30页

作者： Haifeng Zhang Yufeng Xie Wei Li Rajni Chibbar Sidong Xiong Jim Xiang Research Unit Health Research DivisionSaskatchewan Cancer AgencyDepartment of Oncology and ImmunologyUniversity of SaskatchewanSaskatoonSask.Canada Research Unit Health Research DivisionSaskatchewan Cancer AgencyDepartment of PathologyUniversity of SaskatchewanSaskatoonSask.Canada Institute of Biology and Medical Sciences Soochow UniversitySuzhouChina

T cells secrete bioactive exosomes(EXO),but the potential immunoregulatory effect of T-cell EXO is largely *** this study,we generated activated ovalbumin(OVA)-specific CD4^(+) T cells in vitro via coculture of OVA-pulsed dendritic cells(DC_(OVA))with naive CD4^(+) T cells derived from OVA-specific T-cell receptor(TCR)transgenic OTII ***4^(+) T-cell EXO were then purified from the CD4^(+) T-cell culture supernatants by differential ***4^(+) T-cell EXO exhibited the‘saucer’shape that is characteristic of EXO with a diameter between 50 and 100 nm,as assessed by electron microscopy,and contained the EXO-associated proteins LAMP-1,TCR and lymphocyte function associated antigen-1(LFA-1),as determined by western *** cytometric analysis showed that CD4^(+) T-cell EXO expressed CD4^(+) T-cell markers(CD4,TCR,LFA-1,CD25 and Fas ligand),but to a lesser extent than CD4^(+) T *** demonstrated that DC_(OVA) took up CD4^(+) T-cell EXO via peptide/major histocompatibility complex(pMHC)II/TCR and CD54/LFA-1 ***-specific CD4^(+) T-cell EXO from OTII mice,but not ConA-stimulated polyclonal CD4^(+) T-cell EXO from wild-type C57BL/6 mice inhibited DC_(OVA)-stimulated in vitro CD4^(+) T-cell proliferation and in vivo CD81 cytotoxic T lymphocyte(CTL)responses and antitumor immunity against OVA-expressing B16 melanoma BL6-10OVA *** addition,EXO derived from a T-cell hybridoma cell line,MF72.2D9,expressing an OVA-specific CD4^(+) TCR,had a similar inhibitory effect as OTII CD4^(+) T-cell EXO on CTL-mediated antitumor *** together,our data indicate that antigen-specific T-cell EXO may serve as a new type of immunosuppressive reagent for use in transplant rejection and treatment of autoimmune diseases.

关键词： antitumor immunity CTL T-cell exosome

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TGR5 deficiency activates antitumor immunity in non-small cell lung cancer via restraining M2 macrophage polarization

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Acta Pharmaceutica Sinica B 2022年第2期12卷 787-800页

作者： Lifang Zhao Hongyan Zhang Xueqing Liu Shan Xue Dongfang Chen Jing Zou Handong Jiang Department of Respiratory and Critical Care Medicine Ren Ji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages,and plays a critical role in regulating inflammatory *** previous work has shown its role in promoting the progression of non-small cell lung cancer(NSCLC),yet the mechanism remains ***,using Tgr5-knockout mice,we show that TGR5 is required for M2 polarization of tumorassociated macrophages(TAMs)and suppresses antitumor immunity in NSCLC via involving TAMsmediated CD8+T cell ***,we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating c AMP-STAT3/STAT6 *** of c AMP production restores M2-like phenotypes in TGR5-deficient *** NSCLC tissues from human patients,the expression of TGR5 is associated with the infiltration of *** co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC ***,this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC,highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.

关键词： TGR5 Bile acids Tumor-associated macrophages(TAMs) Tumor microenvironment(TME) Non-small cell lung cancer(NSCLC) antitumor immunity Immunotherapy c AMP-STAT3/STAT6

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