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The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface Institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment immune suppression immune escape Clinical treatment Targeting drugs

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Tricking the tumour microenvironment into becoming our best rational drug design factory:reversal of immune suppression

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Journal of Cancer Metastasis and Treatment 2022年第1期8卷 615-623页

作者： Martin L.Ashdown Faculty of Medicine Dentistry and Health SciencesUniversity of MelbourneMelbourne 3011Australia

The immune cellular components of the tumour microenvironment are a diverse group of cells that paradoxically are now appreciated to have a coordinated opposing duality of either promoting or retarding tumour growth.Manipulating this seemingly dynamic interaction for therapeutic benefit is a hotbed of much research.Recent findings in tumour immunology(both preclinical and clinical)build on more than a century of insights and provide a way forward to improving patient outcomes,long term survival and the predictability of“cures”.This opinion piece attempts to summarise some of these historical and contemporary insights with a view to describing eminently testable therapeutic solutions.

关键词： Tumour microenvironments immune suppression regulatory T cells immune modulation reversal plasticity spatio-temporal

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Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression,angiogenesis,invasion and metastasis

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Journal of Genetics and Genomics 2010年第7期37卷 423-430页

作者： Xian-Zong Ye Shi-Cang Yu Xiu-Wu Bian Institute of Pathology and Southwest Cancer Center Southwest Hospital Third Military Medical University Chongqing 400038 China

Growing evidence suggests that myeloid-derived suppressor cells （MDSCs）,which have been named ＂immature myeloid cells＂ or ＂myeloid suppressor cells＂（MSCs）,play a critical role during the progression of cancer in tumor-bearing mice and cancer patients.As their name implies,these cells are derived from bone marrow and have a tremendous potential to suppress immune responses.Recent studies indicated that these cells also have a crucial role in tumor progression.MDSCs can directly incorporate into tumor endothelium.They secret many pro-angiogenic factors as well.In addition,they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases （MMPs）,chemoattractants and creating a pre-metastatic environment.Increasing evidence supports the idea that cancer stem cells （CSCs） are responsible for tumorigenesis,resistance to therapies,invasion and metastasis.Here,we hypothesize that CSCs may ＂hijack＂ MDSCs for use as alternative niche cells,leading to the maintenance of stemness and enhanced chemo-and radio-therapy resistance.The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis.Therefore,the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.

关键词： myeloid-derived suppressor cells immune suppression angiogenesis invasion metastasis

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immune suppression effect on the total alkaloid from decoction of traditional Chinese Medicine Stephania tetrandra S.Moore

Immune suppression effect on the total alkaloid from decocti...

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第十届全国免疫学学术大会

作者： Meng Wang Qing Wei Jing Li Qiuhong Wang Bingyou Yang Haixue Kuang Heilongjiang University of Chinese Medicine

Background:Stephania tetrandra S.Moore(ST),a kind of traditional Chinese herbal medicine(TCHM).It has been used in China for more than 2000 years.The root is the main medicinal part which is used to treat rheumatism,eczema and so on.Related research suggested that therapeutic effect of ST may be related to immune suppression.The clinical application of TCHM stresses on the mode of administration.Based on the traditional mode of administration,boiling water is always used in clinical,which is different from ethanol extraction of Chinese medicine and more accurate and objective characterizes the role of active ingredients of traditional Chinese medicine into body.Objective:Observe the immune response on the nonspecific immunity and specific immunity of total alkaloid from decoction of ST.Method:Using 732 type cation resin enriched total alkaloid in decoction of ST.Then application of carbon clearance method determined clearance index,corrected clearance index and organ index(spleen,thymus).Using hemolysin antibody induced by SRBC measured the content of HCIg.Further study on con A/LPS-induced spleen cells experiment determined the rates of proliferation inhibition.Results:Clearance index,corrected clearance index and organ index expressed immune suppression.The contents of HCIg were 143.2±3.24,172.90±4.06,179.01±4.21,respectively.The rate of con A-induced was 20.63%,24.67%,39.97%.The rate of LPS-induced was 17.82%,18.45%,25.40%.Conclusion:The total alkaloid from decoction of ST had immune suppression activity in non-specific immunity,humoral immune and cellular immune.

关键词： Stephania tetrandra S.Moore alkaloid immune suppression

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Emerging roles of plasmacytoid dendritic cell crosstalk in tumor immunity

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Cancer Biology & Medicine 2023年第10期20卷 728-747页

作者： Leilei Yang Songya Li Liuhui Chen Yi Zhang Biotherapy Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Department of Stomatology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

Plasmacytoid dendritic cells(pDCs)are a pioneer cell type that produces type I interferon(IFN-I)and promotes antiviral immune responses.However,they are tolerogenic and,when recruited to the tumor microenvironment(TME),play complex roles that have long been a research focus.The interactions between p DCs and other components of the TME,whether direct or indirect,can either promote or hinder tumor development;consequently,p DCs are an intriguing target for therapeutic intervention.This review provides a comprehensive overview of p DC crosstalk in the TME,including crosstalk with various cell types,biochemical factors,and microorganisms.An in-depth understanding of p DC crosstalk in TME should facilitate the development of novel p DC-based therapeutic methods.

关键词： Plasmacytoid dendritic cell tumor microenvironment cell crosstalk immune activation immune suppression

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Erythroid Lineage Cells in the Liver:Novel immune Regulators and Beyond

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Journal of Clinical and Translational Hepatology 2020年第2期8卷 177-183页

作者： Li Yang Kyle Lewis Division of Gastroenterology Hepatology and NutritionCincinnati Children’s Hospital Medical CenterCincinnatiOHUSA Division of Gastroenterology Hepatology&Nutrition Developmental Biology Center for Stem Cell and Organoid MedicineCincinnati Children’s Hospital Medical CenterCincinnatiOHUSA

The lineage of the erythroid cell has been revisited in recent years. Instead of being classified as simply inert oxygen carriers, emerging evidence has shown that they are a tightly regulated in immune potent population with potential devel-opmental plasticity for lineage crossing. Erythroid cells have been reported to exert immune regulatory function through secreted cytokines, or cell-cell contact, depending on the conditions of the microenvironment and disease models. In this review, we explain the natural history of erythroid cells in the liver through a developmental lens, as it offers perspec-tives into newly recognized roles of this lineage in liver biology. Here, we review the known immune roles of erythroid cells and discuss the mechanisms in the context of disease models and stages. Then, we explore the capability of erythroid lineage as a cell source for regenerative medicine. We propose that the versatile lineage of erythroid cells provides an underappreciated and potentially promising area for basic and translational research in the field of liver disease.

关键词： Erythroblast immune suppression Liver inflammation Hepatogenesis

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Dynamic Behavior and Function of Foxp3^+ Regulatory T Cells in Tumor Bearing Host

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Cellular & Molecular Immunology 2009年第1期6卷 3-13页

作者： F. Xiao-Feng Qin Department of Immunology The University of TexasMD Anderson Cancer Center The University of Texas Graduate School of Biomedical Sciences at Houston

Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. Growing body of evidence from both laboratory and clinical investigations has demonstrated that expansion and accumulation of these immunosuppressive cells correlates with advanced tumor growth and predicts poor disease prognosis. How tumor development subverts normal self-tolerance function of Tregs thereby thwarts host anti-tumor immunity remains elusive. This review will discuss our current knowledge in understanding the dynamics and plasticity of Foxp3~ Treg activation and induction in tumor bearing hosts and their interaction with various antigen presenting cells （APCs） in tumor microenvironment leading to the establishment of active local and systemic immune suppression. Cellular ＆ Molecular Immunology.

关键词： Treg APC tumor microenvironment immune suppression anti-tumor immunity

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The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody

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Protein & Cell 2012年第6期3卷 441-449页

作者： Meng Xu Xuexiang Du Mingyue Liu Sirui Li Xiaozhu Li Yang-Xin Fu Shengdian Wang Key Laboratory of Infection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Graduate School of the Chinese Academy of Sciences Chinese Academy of SciencesBeijing 100049China Department of Pathology and Committee on Immunology University of ChicagoChicagoIL 60637USA

It has been well established that immune surveillance plays critical roles in preventing the occurrence and prog-ression of tumor.More and more evidence in recent years showed the host anti-tumor immune responses also play important roles in the chemotherapy and radiotherapy of cancers.Our previous study found that tumor-targeting therapy of anti-HER2/neu mAb is mediated by CD8+T cell responses.However,we found here that enhancement of CD8+T cell responses by combination therapy with IL-15R/IL-15 fusion protein or anti-CD40,which are strong stimultors for T cell responses,failed to promote the tumor therapeutic effects of anti-HER2/neu mAb.Analysis of tumor microenviornment showed that tumor tissues were heavily infiltrated with the immunosuppressive macrophages and most tumor infiltrating T cells,especially CD8^(+)T cells,expressed high level of inhibitory co-signaling receptor PD-1.These data suggest that tumor microenvironment is dominated by the immunosuppressive strategies,which thwart anti-tumor immune responses.Therefore,the successful tumor therapy should be the removal of inhibitory signals in the tumor microenvir-onment in combination with other therapeutic strategies.

关键词： anti-HER2/neu antibody CD8^(+)T cells tu-mor microenvironment tumor therapy immune suppression

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The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

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Cellular & Molecular Immunology 2018年第5期15卷 421-427页

作者： Eslam Mohamed Amir A.Al-Khami Paulo C.Rodriguez lee moffitt cancer center and research institute 12902 magnolia dr.mrc-annex 2ndtampafl 33612usa stanley s.scott cancer center louisiana state university health sciences centernew orleansla 70112usa

Malignant cells upregulate distinct energy metabolism programs that support their proliferation,migration,and adaptation to the stressful tumor microenvironment(TME).Additionally,this exaggerated metabolic activity allows cancer cells to hijack essential nutrients and outcompete neighboring infiltrating immune cells,thereby impairing antitumor immunity.During recent years,there has been great interest in the field to understand the tumor-induced energy metabolism signals that regulate the function of immune cells in individuals with cancer.Accordingly,it is now well accepted that uncovering the mechanisms that instruct the metabolic behavior of cancer cells and tumor-associated immune cells is an indispensable strategy for the development of new approaches to overcome immune suppression in tumors.Thus,in this minireview,we briefly discuss the interaction between particular metabolic signaling pathways and immunosuppressive activity in different subsets of myeloid cells within the TME.Additionally,we illustrate potential central mechanisms controlling the metabolic reprogramming of myeloid cells in response to tumor-derived factors.

关键词： Tumor microenvironment metabolic reprogramming immune suppression myeloid cells

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Intercellular Trogocytosis Plays an Important Role in Modulation of immune Responses

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Cellular & Molecular Immunology 2008年第4期5卷 261-269页

作者： Khawaja Ashfaque Ahmed Manjunatha Ankathatti Munegowda Jim Xiang Research Unit Saskatchewan Cancer AgencyDepartments of OncologyMicrobiology and ImmunologyCollege of MedicineUniversity of Saskatchewan20 Campus DriveSaskatoon Saskatchewan S7N 4H4Canada Research Unit Saskatchewan Cancer AgencyDepartments of OncologyMicrobiology and ImmunologyCollege of MedicineUniversity of Saskatchewan20 Campus Drive SaskatoonSaskatchewan S7N 4H4Canada

Intercellular communication is an important means of molecular information transfer through exchange of membrane proteins from cells to cells. Advent of the latest analytical and imaging tools has allowed us to enhance our understanding of the cellular communication through the intercellular exchange of intact membrane patches, also called trogocytosis, which is a ubiquitous phenomenon. immune responses against pathogens or any foreign antigens require fine immune regulation, where cellular communications are mediated by either soluble or cell surface molecules. It has been demonstrated that the membrane molecule transfer between immune cells such as dendritic and T cells can be derived through internalization/recycling pathway, dissociation-associated pathway, uptake of exosomes and membrane nanotube formations. Recent evidence implicates the trogocytosis as an important mechanism of the immune system to modulate immune responses. Exchange of membrane molecules/ antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. In this review, we discuss the possible mechanisms of trogocytosis and its physiological relevance to immune system, with special reference to T cells and the stimulatory or suppressive immune responses derived from T cells with acquired dendritic cell membrane molecules. Cellular ＆ Molecular Immunology. 2008;5（4）：261-269.

关键词： cellular interaction membrane molecule transfer CTL response immune suppression

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