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Mature dendritic cell-derived dendrosomes swallow oxaliplatin-loaded nanoparticles to boost immunogenic chemotherapy and tumor antigen-specific immunotherapy

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Bioactive Materials 2022年第9期7卷 15-28页

作者： Xing Chen Xiang Ling Jiaxuan Xia Ying Zhu Longlong Zhang Yuwei He Anni Wang Guolong Gu Bo Yin Jianxin Wang Department of Pharmaceutics School of PharmacyFudan UniversityKey Laboratory of Smart Drug DeliveryMinistry of EducationShanghai201203China Department of Pharmaceutics School of PharmacyChina Pharmaceutical UniversityState Key Laboratory of Natural MedicinesNanjing210009China Department of Radiology Huashan HospitalFudan UniversityShanghai200040China Institutes of Integrative Medicine of Fudan University Shanghai200040China

The cytomembrane-derived delivery platform represents a promising biomimetic strategy in oncotherapy.To achieve durable and reliable tumor inhibition,mature dendrosomes(mDs),which were isolated from bone marrow-derived dendritic cells undergoing CT26 tumor antigen(TA)stimulation,were fused with redox-responsive nanoparticles(NPs)that were composed of poly(disulfide ester amide)polymers with an intensified disulfide density and hydrophobic oxaliplatin(OXA)prodrugs with the ability to potentiate immunogenicity.In vitro and in vivo results revealed that NP/mDs could induce tumor cell death through mitochondrial pathway and thus created immunogenic microenvironments,but also elicited immunocyte differentiation by TA cross-dressing and infiltration by direct presentation.By further neutralizing immune-regulatory interaction,the administration of PD-L1 antibody(αPD-L1)greatly improved antitumor efficiency of NP/mDs.Furthermore,the effectors of host immune systems effectively inhibited the growth and metastasis of distal tumors,likely because the autologous TA evoked by OXA and allogeneic TA delivered by mDs acted as additional stimuli to reinforce the immune response of tumor-specific T cells and immunosurveillance toward oncogenesis.These results demonstrated that NP/mDs could simultaneously realize immunogenic chemotherapeutics and specific TA delivery.In combination withαPD-L1,the antitumor effect was further enhanced.Therefore,NP/mDs provide a promising strategy for the comprehensive treatment of malignancy.

关键词： dendritic cell Dendrosome Antigen delivery Immunotherapy Chemotherapy

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dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

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cellular & Molecular Immunology 2021年第9期18卷 2128-2139页

作者： Alberto Pérez-Gómez Joana Vitallé Carmen Gasca-Capote Alicia Gutierrez-Valencia María Trujillo-Rodriguez Ana Serna-Gallego Esperanza Muñoz-Muela María de los Reyes Jiménez-Leon Mohamed Rafii-El-Idrissi Benhnia Inmaculada Rivas-Jeremias Cesar Sotomayor Cristina Roca-Oporto Nuria Espinosa Carmen Infante-Domínguez Juan Carlos Crespo-Rivas Alberto Fernández-Villar Alexandre Pérez-González Luis Fernando López-Cortés Eva Poveda Ezequiel Ruiz-Mateos JoséMiguel Cisneros Sonsoles Salto-Alejandre Judith Berastegui-Cabrera Pedro Camacho-Martínez Carmen Infante-Domínguez Marta Carretero-Ledesma Juan Carlos Crespo-Rivas Eduardo Márquez JoséManuel Lomas Claudio Bueno Rosario Amaya JoséAntonio Lepe Jerónimo Pachón Elisa Cordero Javier Sánchez-Céspedes Manuela Aguilar-Guisado Almudena Aguilera Clara Aguilera Teresa Aldabo-Pallas Verónica Alfaro-Lara Cristina Amodeo Javier Ampuero María Dolores Avilés Maribel Asensio Bosco Barón-Franco Lydia Barrera-Pulido Rafael Bellido-Alba Máximo Bernabeu-Wittel Candela Caballero-Eraso Macarena Cabrera Enrique Calderón Jesús Carbajal-Guerrero Manuela Cid-Cumplido Yael Corcia-Palomo Juan Delgado Antonio Domínguez-Petit Alejandro Deniz Reginal Dusseck-Brutus Ana Escoresca-Ortega Fátima Espinosa Nuria Espinosa Michelle Espinoza Carmen Ferrándiz-Millón Marta Ferrer Teresa Ferrer Ignacio Gallego-Texeira Rosa Gámez-Mancera Emilio García Horacio García-Delgado Manuel García-Gutiérrez María Luisa Gascón-Castillo Aurora González-Estrada Demetrio González Carmen Gómez-González Rocío González-León Carmen Grande-Cabrerizo Sonia Gutiérrez Carlos Hernández-Quiles Inmaculada Concepción Herrera-Melero Marta Herrero-Romero Luis Jara Carlos Jiménez-Juan Silvia Jiménez-Jorge Mercedes Jiménez-Sánchez Julia Lanseros-Tenllado Carmina López Isabel López Álvaro López-Barrios Luis F.López-Cortés Rafael Luque-Márquez Daniel Macías-García Guillermo Martín-Gutiérrez Luis Martín-Villén JoséMolina Aurora Morillo María Dolores Navarro-Amuedo Dolores Nieto-Martín Francisco Ortega María Paniagua-García Amelia Peña-Rodríguez E Clinical Unit of Infectious Diseases Microbiology and Preventive MedicineInstitute of Biomedicine of Seville(IBiS)Virgen del Rocío University HospitalCSICUniversity of SevilleSevilleSpain Department of Medical Biochemistry Molecular Biologyand ImmunologySchool of MedicineUniversity of SevilleSevilleSpain Pneumology Service Galicia Sur Health Research Instituto(IIS Galicia Sur)SERGAS-UVigoVigoSpain Infectious Diseases Unit Department of Internal MedicineComplexo HospitalarioUniversitario de VigoIIS Galicia SurSERGAS-UVigoVigoSpain Group of Virology and Pathogenesis Galicia Sur Health Research Institute(IIS Galicia Sur)-Complexo Hospitalario Universitario de VigoSERGAS-UVigoVigoSpain Unit of Infectious Diseases Microbiologyand Preventive MedicineVirgen del Rocío University HospitalSevilleSpain Institute of Biomedicine of Seville(IBiS) Virgen del Rocío University Hospital/CSIC/University of SevilleSevilleSpain Medico-Surgical Unit of Respiratory Diseases Virgen del Rocío University HospitalSevilleSpain Unit of Emergencies Virgen del Rocío University HospitalSevilleSpain Intensive Care Unit Virgen del Rocío University HospitalSevilleSpain Department of Medicine University of SevilleSevilleSpain Cardiology and Cardiovascular Surgery Unit Virgen del Rocío University HospitalSevilleSpain Rheumatology Unit Virgen del Rocío University HospitalSevilleSpain Internal Medicine Unit Virgen del Rocío University HospitalSevilleSpain Digestive and Hepatobiliary Unit Virgen del Rocío University HospitalSevilleSpain Neurology and Clinical Neurophysiology Unit Virgen del Rocío University HospitalSevilleSpain Endocrinology and Nutrition Unit Virgen del Rocío University HospitalSevilleSpain Urology and Nephrology Unit Virgen del Rocío University HospitalSevilleSpain Unit of Clinical Investigation and Clinical Trials Virgen del Rocío University HospitalSevilleSpain

Severe Acute Respiratory Syndrome Coronavirus(SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components.dendritic cells(DCs)play a key role in the defense against viral infections,for instance plasmacytoid DCs(pDCs),have the capacity to produce vast amounts of interferon-alpha(IFN-α).In COVID-19 there is a deficit in DC numbers and IFN-αproduction,which has been associated with disease severity.In this work,we described that in addition to the DC deficiency,several DC activation and homing markers were altered in acute COVID-19 patients,which were associated with multiple inflammatory markers.Remarkably,previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+myeloid DCs and pDCs seven months after SARS-CoV-2 infection.Moreover,the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients,while no restoration of integrinβ7 and indoleamine 2,3-dyoxigenase(IDO)levels were observed.These findings contribute to a better understanding of the immunological sequelae of COVID-19.

关键词： SARS-CoV-2 COVID-19 dendritic cell Long-COVID

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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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HSP70L1-mediated intracellular priming of dendritic cell vaccination induces more potent CTL response against cancer

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cellular & Molecular Immunology 2018年第2期15卷 135-145页

作者： Shuxun Liu Lin Yi Ma Ling Jinxia Jiang Lijun Song Juan Liu Xuetao Cao National Key Laboratory of Medical Immunology Institute of ImmunologySecond Military Medical UniversityShanghai200433China Department of Immunology National Key Laboratory of Medical Molecular BiologyChinese Academy of Medical SciencesBeijing100730China

Heat-shock protein(HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells(DCs).Our previous studies indicate that DCs pulsed with recombinant fusion proteins of antigenic fragment and HSP70-like protein 1(HSP70L1)are potent in stimulating antigen-specific Th1 responses.We herein evaluated the cytotoxic T cell(CTL)response by an intracellular approach of priming DCs with transfection of recombinant adenovirus-expressing the fusion gene of the 576–699 fragment of carcinoembryonic antigen(CEA)and HSP70L1.As compared with DCs pulsed with extracellular fusion protein,the DCs transfected with recombinant adenovirus expressing the fusion gene displayed equivalent mature phenotypes but less inflammatory appearance.However,the transfected DCs were superior to the pulsed DCs in inducing CEA-specific CTLs.Consistently,immunization of HLA-A2.1/H-2Kb transgene mice with the transfected DCs could induce more quantities of HLA-A2.1-restricted CEA-specific CTLs,protecting nude mice more significantly from human CEA-expressing colon tumor challenge when adoptively transferred.Mechanistic investigation indicated that intracellular expression of the fusion protein empowered the transfected DCs by activation of STAT1 possibly via inducing IFN-βand ERK pathways.Therefore,the more potent ability to induce anti-CEA CTL responses enables the DCs,which transfected with recombinant adenovirus expressing the fusion gene of antigenic CEA fragment and Th1 adjuvant,as an alternative promising approach for the immunotherapy of CEA-positive tumors.

关键词： CTL dendritic cell HSP70L1 immunotherapy

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The development and function of dendritic ce ）opulations and their regulation by miRNAs

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Protein & cell 2017年第7期8卷 501-513页

作者： Haibo Zhou Li Wu Tsinghua-Peking Joint Center for Life Sciences Tsinghua University School of Medicine Institute of Immunology Tsinghua University Beijing 100084 China

dendritic cells （DCs） are important immune cells linking innate and adaptive immune responses. DCs encounter various self and non-self antigens present in the envi- ronment and induce different types of antigen specific adaptive immune responses. DCs can be classified into lymphoid tissue-resident DCs, migratory DCs, non-lym-phoid resident DCs, and monocyte derived DCs （moDCs）. Recent work has also established that DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte func- tion. The development of different DC subsets has been found to be regulated by a network of different cytokines and transcriptional factors. Moreover, the response of DC is tightly regulated to maintain the homeostasis of immune system. MicroRNAs （miRNAs）are an important class of cellular regulators that modulate gene expres- sion and thereby influence cell fate and function. In the immune system, miRNAs act at checkpoints during hematopoietic development and cell subset differentia- tion, they modulate effector cell function, and are implicated in the maintenance of homeostasis. DCs are also regulated by miRNAs. In the past decade, much progress has been made to understand the role of miRNAs in regulating the development and function of DCs. In this review, we summarize the origin and dis- tribution of different mouse DC subsets in both lym- phoid and non-lymphoid tissues. The DC subsets identified in human are also described. Recent progress on the function of miRNAs in the development and activation of DCs and their functional relevance to autoimmune diseases are discussed.

关键词： dendritic cell mirna activation,development autoimmUne disease

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dendritic cell as Therapeutic Vaccines against Tumors and Its Role in Therapy for Hepatocellular Carcinoma

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cellular & Molecular Immunology 2006年第3期3卷 197-203页

作者： Kang Sun Liang Wang Yanyun Zhang Department of General Surgery the First Affiliated Hospital of Soochow University Suzhou 215006 China Shanghai Institute of Immunology Medical School of Shanghai Jiaotong University Shanghai 200025 China

dendritic cells （DCs） are the most potent professional antigen-presenting cells, and capable of stimulating naive T cells and driving primary immune responses. DCs are poised to capture antigen, migrate to draining lymphoid organs, and after a process of maturation, select antigen-specific lymphocytes to which they present the processed antigen, thereby inducing immune responses. The development of protocols for the ex vivo generation of DCs may provide a rationale for designing and developing DC-based vaccination for the treatment of tumors. There are now several strategies being applied to upload antigens to DCs and manipulate DC vaccines. DC vaccines are able to induce therapeutic and protective antitumor immunity. Numerous studies indicated that hepatocellular carcinoma （HCC） immunotherapies utilizing DC-presenting tumor-associated antigens could stimulate an antitumour T cell response leading to clinical benefit without any significant toxicity. DC-based tumor vaccines have become a novel immunoadjuvant therapy for HCC. cellular ＆ Molecular Immunology. 2006;3（3）：197-203.

关键词： dendritic cell vaccination hepatocellular carcinoma

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Osthole treatment ameliorates Th2-mediated allergic asthma and exerts immunomodulatory effects on dendritic cell maturation and function

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cellular & Molecular Immunology 2017年第11期14卷 935-947页

作者： Chen-Yuan Chiang Chen-Chen Lee Chia-Kwung Fan Huei-Mei Huang Bor-Luen Chiang Yueh-Lun Lee Division of Pulmonary Medicine Department of Internal MedicineWan Fang HospitalTaipei Medical UniversityTaipei 11031TaiwanChina Department of Internal Medicine School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina Department of Microbiology and Immunology School of MedicineCollege of MedicineChina Medical UniversityTaichung 40402TaiwanChina Department of Parasitology School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina Graduate Institute of Medical Sciences College of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina Graduate Institute of Clinical Medicine College of MedicineNational Taiwan UniversityTaipei 10048TaiwanChina Department of Microbiology and Immunology School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina

Osthole,an active component of Chinese herbal medicines,reportedly possesses various pharmacological properties and has potential therapeutic applications.This study explored the anti-allergic effects of osthole in asthmatic mice and investigated the immunomodulatory actions of osthole on dendritic cells(DCs)and T cells.Herein,we show that oral administration of osthole to BALB/c mice after ovalbumin(OVA)sensitization ameliorated all of the cardinal features of T helper 2(Th2)-mediated allergic asthma;namely,the production of OVA-specific immunoglobulin E,airway hyperresponsiveness,airway inflammation and the production of Th2-type cytokines including interleukin(IL)-4,IL-5 and IL-13.Surprisingly,IL-10 production was not inhibited and was even enhanced by osthole treatment.We observed a significant increase in the percentages of IL-10-producing DCs and forkhead box P3-positive regulatory T(Treg)cells in osthole-treated asthmatic mice.Additionally,in vitro analyses revealed that osthole-treated bone-marrow-derived DCs had a partial maturation phenotype,secreting large amounts of IL-10 and low levels of proinflammatory cytokines,such as IL-12,IL-6 and tumor necrosis factor-α,and displaying reduced levels of MHC class II surface molecules.These DCs displayed immunosuppressive capacity by directly inhibiting effector T-cell responses or inducing Treg cells.In addition,osthole directly inhibited the activated CD4+T-cell proliferation and Th1/Th2-type cytokine production in this system.Collectively,these results suggest that DCs and T cells are potential target cells responsible for the action of osthole against allergic asthma.

关键词： asthma dendritic cell osthole T cell

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The kinase p38αfunctions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation

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cellular & Molecular Immunology 2022年第7期19卷 805-819页

作者： Miaomiao Han Jingyu Ma Suidong Ouyang Yanyan Wang Tingting Zheng Peishan Lu Zihan Zheng Weiheng Zhao Hongjin Li Yun Wu Baohua Zhang Ran Hu Kinya Otsu Xinguang Liu Ying Wan Huabin Li Gonghua Huang ENT Institute and Department of Otorhinolaryngology Eye&ENT HospitalFudan University200031 ShanghaiChina Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine200025 ShanghaiChina Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University523808 DongguanChina Biomedical Analysis Center Army Medical University400038 ChongqingChina Department of Cardiovascular Medicine Graduate School of MedicineOsaka UniversityOsaka 565-0871Japan School of Cardiovascular Medicine and Sciences King’s College LondonLondon SE59NUUK Present address:Tongji Hospital Tongji Medical CollegeHuazhong University of Science and Technology430030 WuhanChina Department of Dermatology Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese Medicine200437 ShanghaiChina Department of Clinical Laboratory Medicine Shanghai Tenth People’s Hospital of Tongji University200072 ShanghaiChina Present address:Basic Department of Cancer Center Shanghai Tenth People’s Hospital of Tongji University200072 ShanghaiChina

dendritic cells(DCs)play a critical role in controlling T helper 2(Th2)cell-dependent diseases,but the signaling mechanism that triggers this function is not fully understood.We showed that p38αactivity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines.p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation.Further study showed that p38αin cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis.Importantly,crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase,not the effector phase,and was conserved between mice and humans.Our results identify p38αsignaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function,and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.

关键词： Allergy p38α dendritic cell Th2

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The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Fit3＋ lymphocyte-primed multipotent precursors

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cellular & Molecular Immunology 2016年第5期13卷 593-604页

作者： Jing Xiao Haibo Zhou Ning Wu Li Wu Tsinghua-Peking Joint Center for Life Sciences Tsinghua University School of Medicine Beijing 100084 China

The differentiation of dendritic cells （DC） is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC （pDC） and CD 172a-CD8a＋conventional DC （cDC） were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Fit3＋ lymphoid-primed multipotent precursors （LMPP）, common lymphoid progenitors （CLP） and common DC precursors （CDP）, were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells （HSC） with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow （BM） HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Fit3, Gfi-1, Ikaros, Bc111a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging.

关键词： aging dendritic cell Wnt5a

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Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

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cellular & Molecular Immunology 2015年第3期12卷 283-291页

作者： Adam J. Gehring June Ann D'Angelo Molecular Microbiology and Immunology Saint Louis University School of Medicine Saint Louis MO USA Saint Louis University Liver Center SaintLouis University School of Medicine Saint Louis MO USA

Therapeutic vaccines to boost endogenous T-cell immunity rely on the stimulatory capacity of dendritic cells （DCs）. The functionality of DCs in chronic hepatitis B virus （HBV） infection has been a long-standing debate. Therefore, we have attempted to summarize multiple studies investigating DC function in chronic HBV patients to determine whether common observations can be drawn. We found that the frequency and function of ex vivo-tested myeloid and plasmacytoid DCs were largely intact in patients with HBV infection and similar to those of healthy donor DCs. The main exception was reduced IFN-a production by plasmacytoid DC from chronic HBV patients. This reduced IFN-a production correlated with liver inflammation in multiple studies but not with viral load, suggesting that viral antigens have little effect on DC function. The majority of the confusion about DC function arises from studies reporting the reduced function of healthy donor DCs exposed to various sources of H BV in vitro. These direct effects of viral antigens are in contrast to data from HBV-infected patients. The variations in the assays used and areas that reauire further investigation are also covered

关键词： Hepatitis B virus dendritic cell Vaccination

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