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World Journal of Gastroenterology 2022年第45期28卷 6345-6355页

作者： Duan-Rui Qiao Guan-Yue Shan Shuai Wang Jun-Ya Cheng Wei-Qun Yan Hai-Jun Li Department of Bioengineering Pharmacy School of Jilin UniversityChangchun 130021Jilin ProvinceChina Institute of Translational Medicine The First Hospital of Jilin UniversityChangchun 130061Jilin ProvinceChina Department of Students Affairs China-Japan Union Hospital of Jilin UniversityChangchun 130031Jilin ProvinceChina Institute of Liver Diseases The First Hospital of Jilin UniversityChangchun 130061Jilin ProvinceChina

The mononuclear phagocyte system(MPS)consists of monocytes,dendritic cells and macrophages,which play vital roles in innate immune defense against cancer.Hepatocellular carcinoma(HCC)is a complex disease that is affected or initiated by many factors,including chronic hepatitis B virus infection,hepatitis C virus infection,metabolic disorders or alcohol consumption.Liver function,tumor stage and the performance status of patients affect HCC clinical outcomes.Studies have shown that targeted treatment of tumor microenvironment disorders may improve the efficacy of HCC treatments.Cytokines derived from the innate immune response can regulate T-cell differentiation,thereby shaping adaptive immunity,which is associated with the prognosis of HCC.Therefore,it is important to elucidate the function of the MPS in the progression of HCC.In this review,we outline the impact of HCC on the MPS.We illustrate how HCC reshapes MPS cell phenotype remodeling and the production of associated cytokines and characterize the function and impairment of the MPS in HCC.

关键词： Mononuclear phagocyte system Hepatocellular carcinoma Monocyte dendritic cell Macrophage

Interactions of Indoleamine 2,3-dioxygenase-expressing LAMP3^(+) dendritic cells with CD4^(+) regulatory T cells and CD8^(+) exhausted T cells:synergistically remodeling of the immunosuppressive microenvironment in cervical cancer and therapeutic implications

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Cancer Communications 2023年第11期43卷 1207-1228页

作者： Xinyu Qu Yumeng Wang Qian Jiang Tingting Ren Chenyan Guo Keqin Hua Junjun Qiu Department of Gynecology Obstetrics and Gynecology HospitalFudan UniversityShanghaiP. R. China Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases ShanghaiP. R. China

Background Cervical cancer(CC)is the fourth most common cancer in women worldwide.Although immunotherapy has been applied in clinical practice,its therapeutic efficacy remains far from satisfactory,necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets.This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets.Methods We conducted single-cell RNA sequencing on a total of 17 clinical specimens,including normal cervical tissues,high-grade squamous intraepithelial lesions,and CC tissues.To validate our findings,we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines(TC1)to evaluate the effectiveness of combination therapy involving indoleamine 2,3-dioxygenase 1(IDO1)inhibition and immune checkpoint blockade(ICB).We used the unpaired two-tailed Student's t-test,Mann-Whitney test,or Kruskal-Wallis test to compare continuous data between two groups and one-way ANOVA with Tukey's post hoc test to compare data between multiple groups.Results Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape,whereas lysosomal-associated membrane protein 3-positive(LAMP3^(+))dendritic cells(DCs)in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism.These cells interacted with both tumor-reactive exhausted CD8^(+)T cells and CD4^(+) regulatory T cells,synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape.Further validation through multicolor immunohistochemical staining showed co-localization of neoantigen-reactive T cells(CD3^(+),CD4^(+)/CD8^(+),and PD-1^(+))and LAMP3+DCs(CD80^(+) and PD-L1^(+)).Additionally,a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone.Conclusions Our study suggested that a combinatio

关键词： cervical cancer dendritic cell immune checkpoint blockade immune escape indoleamine 2,3-dioxygenase 1 single-cell analysis T cell

dendritic cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

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cellular & Molecular Immunology 2009年第2期6卷 87-95页

作者： Hong Fu Shaohua Song Fang Liu Zhijia Ni Xiaoyun Shen Liang Xiao Guoshan Ding Quanxing Wang Center for Organ Transplantation of Changzheng Hospital Second MilitaryMedical University Shanghai 200003 China Institute of Immunology Second Military Medical University Shanghai 200433 China Hong Fu and Shaohua Song contributed equally to this study

SOCS1 is a key regulator of cytokine signaling and is important for maintaining balance in the immune system. It is thought to participate in negative feedback loops in cytokine signaling and may be an important signal for the regulation of dendritic cell （DC） maturation. However, it remains unclear whether DCs transduced with SOCS1 exhibit characteristics of regulatory DCs and induce allogeneic T-cell hyporesponsiveness. In this study, we constructed adenovirai vector coding SOCS1 （Ad-SOCS1） that can efficiently increase SOCS1 gene expression in bone marrow-derived dendritic cells. DCs transduced with Ad-SOCS1 （DC-SOCS1） expressed low levels of costimulatory and MHC molecules, were resistant to maturation and activation stimulation, induced allogeneic T-cell hyporesponsiveness, and promoted the generation of regulatory-like T cells in vitro. DC-SOCS1 pretreatment significantly prolonged the survival of ailografts and led to a substantial increase in the generation of regulatory T cells. Our data suggest that SOCS1 inhibits DC maturation and induces regulatory DC generation, therefore possessing therapeutic potential to prevent rejection in organ transplantation.

关键词： dendritic cell SOCS 1 tolerance regulatory dendritic cell allograft survival

Exosomes derived from rAAV/AFP-transfected dendritic cells elicit specific T cell-mediated immune responses against hepatocellular carcinoma

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Exosomes derived from rAAV/AFP-transfected dendritic cells e...

dendritic cells as Vectors for Immunotherapy of Tumor and Its Application for Gastric Cancer Therapy

2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青...

作者： Jie-Yu Li Sheng-Lan Huang Zhi-Feng Zhou Wan-Song Lin Shu-Ping Chen Ming-Shui Chen Yun-Bin Ye School of Basic Medical Sciences Fujian Medical University Laboratory of Immuno-Oncology Fujian Cancer Hospital & Fujian Medical University Cancer Hospital Fujian Key Laboratory of Translational Cancer Medicine

dendritic cell（DC）-derived exosomes（Dex） have been proved to induce and enhance antigen-specific T cell responses in vivo, and previous clinical trials have shown the feasibility and safety of Dex in multiple human cancers. However, there is little knowledge on the efficacy of Dex against hepatocellular carcinoma（HCC） until now. In this study, human peripheral blood-derived DCs were loaded with recombinant adenoassociated viral vector（r AAV） carrying alpha-fetoprotein（AFP） gene（rAAV/AFP）, and high-purity Dex were generated. Then, na?ve T cells were stimulated with Dex, to investigate the specific T cell-mediated immune responses against HCC. Our findings showed that Dex were effective to stimulate na?ve T cell proliferation, and induce T cell activation to become antigen-specific cytotoxic T lymphocytes（CTLs）, thereby exhibiting anti-tumor immune responses against HCC. In addition, Dex-sensitized DC precursors seemed more effective to trigger major histocompatibility complex class I（MHC I）-restricted CTL response and allow DCs to make full use of the minor antigen peptides, thereby maximally activating specific immune responses against HCC. It is concluded that Dex, which combine the advantages of DCs and cell-free vectors, are promising to completely, or at least in part, replace mature DCs to function as cancer vaccines or natural antitumor adjuvant.

关键词： Hepatocellular carcinoma dendritic cell Exosome Immune response Cytotoxic T lymphocyte

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cellular & Molecular Immunology 2004年第5期1卷 351-356页

作者： YugangWu LiangWang YanyunZhang Department ofGeneralSurgerytheFirstAffiliatedHospitalofSoochowUniversitySuzhouJiangsu215006China. HealthScienceCenterofShanhaiInstitutesforBiologicalSciences ChineseAcademyofSciencesShanghai200025China.

dendritic cells(DCs) are recognized as the most potent antigen-presenting cells(APCs) with the ability to stimulate naive resting T cells and initiate primary immune responses.DCs are poised to capture antigen(Ag), migrate to draining lymphoid organs,and,after a process of maturation,select Ag-specific lymphocytes to which they present the processed Ag,thereby inducing immune responses.Numerous studies indicated that immunotherapies utilizing DC-presenting tumor-associated antigens can safely be administered to cancer patients and induce significant immunologic and clinical responses.Moreover,it has been demonstrated that DCs are related to clinical stage,invasion,metastasis and prognosis of gastric cancer.DC-based tumor vaccines become a new effective immunoadjuvant therapy for gastric cancer.cellular & Molecular Immunology.2004; 1(5):351-356.

关键词： dendritic cell vaccination gastric cancer

dendritic cells as a Pharmacological Target of Traditional Chinese Medicine

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cellular & Molecular Immunology 2006年第6期3卷 401-410页

作者： Xin Chen Lu Yang O. M. Zack Howard Joost J. Oppenheim Basic Research Program SAIC-Frededck Inc. NCI-Frederick ImQuest BioSciences Inc. 7340 Executive Way Frederick MD 21704 Laboratory of Molecular Immunoregulation Center for Cancer Research NCI-Frederick Frederick Maryland 21702-120

dendritic cells （DCs） represent a heterogeneous population of professional antigen-presenting cells （APCs） that play a central role in the initiation and regulation of immune responses. There is considerable evidence that DCs can be used as therapeutic targets for pharmacological modulation of immune responses. Traditional Chinese medicine （TCM） has a long-standing history of using herbal medicine in the treatment of variety of human diseases. Many of the clinical effects of TCM have reportedly been attributed to the up- or down-regulation of immune responses. Accumulating evidence indicates that TCM and its components can interfere with immune responses at the earliest stage by targeting key functions of DCs. Here, we review those published studies of TCM with respect to their effects on immunobiological functions of DCs. Investigations based on both chemical entities derived from TCM as well as TCM herbal mixtures are presented. These studies suggest that various TCM herbal medicines have the capacity to inhibit or promote major functions of DCs, such as differentiation, maturation, cytokine production, survival, antigen uptake and presentation as well as trafficking. These studies have revealed novel biological effects of TCM and documented the utility of this approach to discover novel biological modifier of DC functions derived from natural sources.

关键词： dendritic cell traditional Chinese medicine

Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse

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cellular & Molecular Immunology 2010年第3期7卷 211-220页

作者： Paul L Bollyky Stephen P Evanko Rebecca P Wu Susan Potter-Perigo S Alice Long Brian Kinsella Helena Reijonen Kelly Guebtner Brandon Teng Christina K Chan Kathy R Braun John A Gebe Gerald T Nepom Thomas N Wight Benaroya Research Institute SeattleWAUSA

Hyaluronan(HA)production by dendritic cells(DCs)is known to promote antigen presentation and to augment T-cell activation and proliferation.We hypothesized that pericellular HA can function as intercellular‘glue’directly mediating T cell–DC binding.Using primary human cells,we observed HA-dependent binding between T cells and DCs,which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone(4-MU),an agent which blocks HA synthesis.Furthermore,T cells regulate HA production by DCs via T cell-derived cytokines in a T helper(Th)subset-specific manner,as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production.Similar effects were seen upon the addition of exogenous Th1 cytokines,IL-2,interferon c(IFN-c)and tumor necrosis factor a(TNF-a).The critical factors which determined the extent of DC–T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA,as T-cell clones which were pre-treated with monensin,added to block cytokine secretion,bound equivalently irrespective of their Th subset.These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA,which in turn affects the extent of DC–T cell binding.We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation.These data point to a pivotal role for HA in DC–T cell interactions at the IS.

关键词： dendritic cell hyaluronan immune synapse pericellular matrix Th1

Antitumor Activity and Immune Enhancement of Murine Interleukin-23 Expressed in Murine Colon Carcinoma cells

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cellular & Molecular Immunology 2006年第1期3卷 47-52页

作者： Baoen Shan Jingsheng Hao Qiaoxia Li Masatoshi Tagawa Research Center the Fourth Hospital of Hebei Medical University Shijiazhuang 050011 Hebei China Division of Pathology Chiba Cancer Research Institute 666-2 Nitona Chuo-ku Chiba 260-6717 Japan

Interleukin （IL）-23, a cytokine composed of p19 and the p40 subunit of IL-12, can enhance the proliferation of memory T cells and production of IFN-γ from activated T cells. It can also induce antitumor effects in murine model. To further evaluate the antitumor activity and immune enhancement of IL-23 in vivo, murine colon carcinoma cells retrovirally transduced with mIL-23 gene were injected subcutaneously （s.c.） into BALB/c mice. Survival time and tumor volume were observed. LDH release assay, [^3H]-TdR incorporation assay and ELISA were used to determine CTL activity, proliferation of splenocytes and level of cytokines, respectively. Number of dendritic cells （DCs） was analyzed by flow cytometry （FCM）. IL-23 secreted by Colon26/IL-23 cells suppressed the growth of tumor and prolonged the survival time of mice, enhanced proliferation of splenocytes, CTL activity, and number of DCs. IL-23 also promoted the production of Thl cytokines such as IFN-γ, IL-12 and TNF-α. However, the level of IL-4 was not enhanced significantly. These data suggested that IL-23 secreted by tumor cells can induce antitumor activitv bv enhancing immune resnonse.

关键词： IL-23 antitumor proliferation cytokine CTL dendritic cell

Murine corneal stroma cells suppress bone marrow-derived dendritic cells maturation in vitro

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Chinese Medical Journal 2012年第11期125卷 2041-2047页

作者： LU Jian-min JIANG Xin-li LIU Jin-ling WANG Hui-fang LI Xiao-lei SONG Xiu-jun Department of Ophthalmology Third Hospital of Hebei Medical University Shijiazhuang Hebei 050051 China Department of Ophthalmology First Affiliated Hospital of Dalian Medical University Dalian Liaoning 116011 China

Background Prostaglandin E2 （PGE2） is a key modulator of dendritic cells （DCs） function, and cornea-derived transforming growth factor beta 2 （TGF-β2） promotes the generation of phenotypically and functionally immature DCs. Therefore, this study was carried out to investigate whether PGE2 is involved in the suppressive effect on DCs maturation mediated by corneal stroma cells （CSCs） and whether PGE2 and TGF-β2 have additive effects in this immunosuppressive mechanism. Methods Bone marrow-derived DCs （BM-DCs）, splenic T cells and CSCs culture supernatant were obtained from mice via various protocols. After that, the level of PGE2 in CSCs culture supernatant was analyzed by enzyme-linked immunosorbent assay. Then, immature BM-DCs pretreated by E-prostanoid 2 receptor antagonist AH6809 or dimethyl sulfoxide were induced to mature in the presence of lipopolysaccharide, with or without CSCs culture supernatant. In parallel experiments, neutralizing TGF-β2 antibody or normal goat IgG was added into the supernatant. Next, the cellular surface markers for DCs maturation, including CD80, CD86, and major histocompatibility complex class Ⅱ （MHC Ⅱ）, were analyzed by flow cytometry; the capability of stimulating the proliferation of T lymphocytes was evaluated by allogeneic mixed lymphocyte reactions and the function of endocytosis was assessed by fluorescein isothiocyanate-dextran uptake. Results Higher concentration of PGE2 was detected in CSCs culture supernatant than in the fresh medium. In addition, compared with control group, after treated with the supernatant in the mature stage, BM-DCs displayed lower expression of CD80, CD86 and MHC Ⅱ, lower T cell stimulatory capacity and higher endocytosis function. However, after the application of AH6809, BM-DCs partially regained T cell stimulatory capacity and expression of CD86 and MHC Ⅱ, but partially lost endocytic activity. Moreover, after the application of AH6809 and neutralizing TGF-β2 antibody, the result of statistical analysis indicated that there was a statistical d

关键词： corneal stroma cell dendritic cell inhibit maturation mouse