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Enforced PGC-1α expression promotes cd8 T cell fitness, memory formation and antitumor immunity

Cellular & Molecular Immunology 2021年第7期18卷 1761-1771页

作者： Nina Dumauthioz Benjamin Tschumi Mathias Wenes Bastien Marti Haiping Wang Fabien Franco Wenhui Li Isabel CLopez-Mejia Lluis Fajas Ping-Chih Ho Alena Donda Pedro Romero Lianjun Zhang Translational Tumor Immunology Group Ludwig Cancer ResearchUniversity of LausanneEpalingesSwitzerland Department of Fundamental Oncology University of LausanneEpalingesSwitzerland Department of Fundamental Oncology University of LausanneEpalingesSwitzerland Ludwig Cancer Research Institute Lausanne BranchEpalingesSwitzerland Center for Systems Medicine Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical College100005BeijingChina Suzhou Institute of Systems Medicine SuzhouJiangsu215123China Center for Integrative Genomics University of LausanneLausanneSwitzerland

Memory cd8 T cells can provide long-term protection against tumors,which depends on their enhanced proliferative capacity,self-renewal and unique metabolic rewiring to sustain cellular ***,memory cd8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic *** contrast,tumor-infiltrating lymphocytes(TILs)display severe metabolic defects,which may underlie their functional ***,we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the master regulator of mitochondrial biogenesis(MB),favors cd8 T cell central memory formation rather than resident memory ***-1α-overexpressing cd8 T cells persist and mediate more robust recall responses to bacterial infection or peptide ***,cd8 T cells with enhanced PGC-1αexpression provide stronger antitumor immunity in a mouse melanoma ***,TILs overexpressing PGC-1αmaintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free ***,our findings indicate that enforcing mitochondrial biogenesis promotes cd8 T cell memory formation,metabolic fitness,and antitumor immunity in vivo.

关键词： PGC-1α Mitochondria cd8 Memory Anti-tumor immunity

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cd8:Adhesion Molecule,Co-Receptor and Immuno-Modulator

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Cellular & Molecular Immunology 2004年第2期1卷 81-88页

作者： David K Cole George F Gao Nuffield Department of Clinical Medicine John Radcliffe HospitalUniversity of OxfordHeadington Oxford OX3 9DUUnited Kingdom.

cd8 is a cell surface glycoprotein found in cytotoxic T lymphocytes,which are important components in cellular immunity,*** the immune response to cancer and chronic *** are two forms of cd8, either as an αα homodimer or αβ *** acts as an“assistant”or co-receptor in the function of cytotoxic T cells where specific immunity is mediated by interaction of specific T cell receptor(αβTCR)and its ligand peptide major histocompatibility complex(pMHC).cd8 also binds to pMHC but away from the interface of pMHC and TCR contact,thereof no influence on the specificity of this *** the TCR and cd8 bind to the same pMHC at the same time,cd8 is defined as a co-receptor,functioning through its signalling via its cytoplasmic tyrosine phosphorylation pathway;if cd8 binds to pMHC independently of the TCR,it is defined as an adhesion *** present,the co-receptor function theory is dominated in the field. Recent study has also shown that murine cd8αα binds to TL antigen,an MHC homologue,therefore acts as an *** this review,we discuss these current understandings of the three aspects of the cd8 functions and their structural *** & Molecular Immunology.2004;1(2):81-88.

关键词： cd8 T cell adhesion co-receptor immuno-modulator

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Proteomic analysis reveals distinctive protein profiles involved in cd8^(+) T cell-mediated murine autoimmune cholangitis

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Cellular & Molecular Immunology 2018年第8期15卷 756-767页

作者： Weici Zhang Ren Zhang Jun Zhang Ying Sun Patrick SC Leung Guo-Xiang Yang Zongwen Shuai William M Ridgway M Eric Gershwin Division of Rheumatology Allergy and Clinical ImmunologyUniversity of CaliforniaDavisCaliforniaUSA Department of Pathogenic Biology and Immunology Guangzhou University of Chinese MedicineGuangzhou 510006China Center for non-infectious liver diseases Beijing 302 HospitalBeijing 100039China Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Division of Immunology Allergy and RheumatologyUniversity of CincinnatiCincinnatiOH 45267

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver,and T cells are critical drivers in this ***,little is known about the regulation of their functional behavior during disease *** previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type Ⅱ(dnTGFβ RII)spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis(PBC).Adoptive transfer of cd8^(+) but not cd4^(+) T cells into Rag1^(−/−)mice reproduced the disease,demonstrating a critical role for cd8^(+) T cells in PBC ***,we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFβRII and B6 control mice at different *** addition,we analyzed cd8 protein profiles after adoptive transfer of splenic cd8^(+) cells into Rag1^(−/−)*** use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of cd8 cells,which are key to biliary *** total,254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic cd8^(+) cells compared to donor splenic cd8^(+) *** contrast to donor splenic cd8^(+) cells,recipient hepatic cd8^(+) cells expressed distinct profiles for proteins involved in chemokine signaling,focal adhesion,T cell receptor and natural killer cell-mediated cytotoxicity pathways.

关键词： autoimmune cholangitis cd8 dnTGFβRII mice proteomic analysis

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cd8^+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model

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Chinese Science Bulletin 2012年第1期57卷 48-53页

作者： YANG YaJun LI XiaoZhu WANG YaoHe WANG ShengDian Key Laboratory oflnfection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Sino-British Research Center for Molecular Oncology Zhengzhou UniversityZhengzhou 450001China Center for Molecular Oncology Barts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK

The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tu- mor model in immunocompetent ***,we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of *** found that cd8+T cells were critical mediator for antitumor efficacy by oncolytic *** viral therapy induced intensive infiltration of cd8+T cells in tumor,increased tumor-specific IFN-?(interferon-?)production and CTL(cytotoxic T lymphocyte)activity of lymphocytes,and generated a long-term tumor-specific immune *** cd8+T cell responses by agonistic anti-4-1BB(cluster differentiation 137,cd137)antibody showed synergistic anticancer effects with oncolytic viro- *** results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.

关键词：腺病毒感染 T细胞反应治疗作用免疫反应小鼠模型 cd8 细胞毒性T淋巴细胞抗肿瘤机制

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Intratumoral cd103^(+)cd8^(+)T cells predict response to neoadjuvant chemoimmunotherapy in advanced head and neck squamous cell carcinoma

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Cancer Communications 2023年第10期43卷 1143-1163页

作者： Siqi Ren Tianjun Lan Fan Wu Suling Chen Xue Jiang Chuying Huo Zitian Li Shule Xie Donghui Wu Ruixin Wang Yanyan Li Lin Qiu Guoxin Huang Shurui Li Xiaojuan Wang Meifeng Cen Tingting Cai Zhaoyu Lin Jinsong Li Bowen Li Department of Oral and Maxillofacial Surgery Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangdongP.R.China Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangdongP.R.China Department of Gynecological Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangdongP.R.China School of Stomatology Jilin UniversityJilinP.R.China Stomatology Hospital of Haizhu district GuangdongP.R.China

Background Immune cell heterogenicity is known to determine the therapeutic response to cancer *** chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is *** efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical ***,we attempted to identify molecules predicting NACI response in advanced *** We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,cd103^(+)cd8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor *** regulatory mechanism of the cd103^(+)cd8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC *** We established intratumoral cd103^(+)cd8^(+)TILs density as a determinant of NACI efficacy in *** scRNA-seq results indicated that the population of cd103^(+)cd8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral cd103^(+)cd8^(+)TILs density and NACI efficacy in HNSCC *** receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to *** assays showed that cd103^(+)cd8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced cd103^(+)cd8^(+)TILs cytotoxicity against tumor growth in ***,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of cd103^(+)cd8^(+)TILs and facilitate antitumor immunity

关键词： cd103 cd8 head and neck squamous cell carcinoma neoadjuvant chemoimmunotherapy predictive marker tumor-infiltrating lymphocyte

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Increased cd4/cd8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer:A prospective pilot study

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World Journal of Gastrointestinal Oncology 2023年第2期15卷 303-317页

作者： Daniel Skubleny Andrea Lin Saurabh Garg Ross McLean Michael McCall Sunita Ghosh Jennifer L Spratlin Daniel Schiller Gina Rayat Department of Surgery University of AlbertaEdmonton T6G 2R3ABCanada Department of Surgery University of AlbertaEdmonton T6G 2R3AlbertaCanada Department of Laboratory Medicine and Pathology University of AlbertaEdmonton T6G 2R3AlbertaCanada Department of Oncology University of AlbertaEdmonton T6G 2R3AlbertaCanada Department of Oncology Cross Cancer InstituteUniversity of AlbertaEdmonton T5G 1Z2ABCanada

BACKGROUND Despite optimal neoadjuvant chemotherapy only 40%of gastric cancer tumours achieve complete or partial treatment *** the absence of treatment response,neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery *** strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy(5-Fluorouracil,Leucovorin,Oxaliplatin and Docetaxel).Predictive biomarkers detected using immunohistochemistry(IHC)methods may provide useful data regarding treatment *** To investigate the utility of cd4,cd8,Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric *** Forty-three adult patients with gastric adenocarcinoma,of which 18 underwent neoadjuvant chemotherapy,were included in a prospective clinical *** biopsies were obtained from gastric cancer and normal adjacent gastric *** in expression of Galectin-3,Ecadherin,cd4^(+)and cd8^(+)molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with *** response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists *** response was defined as complete or near complete tumour response,whereas partial or poor/no response was defined as *** IHC images were annotated and quantitatively assessed using QuPath *** expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon *** expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after *** performed a preliminary multivariate analysis and power analysis to guide future *** analyses were completed using R *** The ratio betw

关键词： cd4 cd8 Galectin-3 Neoadjuvant chemotherapy Treatment response Gastric cancer

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Therapeutic effect of curcumin on experimental colitis mediated by inhibiting cd8^+ cd11c^+ cells

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World Journal of Gastroenterology 2017年第10期23卷 1804-1815页

作者： Hai-Mei Zhao Fei Han Rong Xu Xiao-Ying Huang Shao-Min Cheng Min-Fang Huang Hai-Yang Yue Xin Wang Yong Zou Han-Lin Xu Duan-Yong Liu School of Basic Medical Sciences Jiangxi University of Traditional Chinese Medicine College of Pharmacy Jiangxi University of Traditional Chinese Medicine College of Pharmacy Hubei University of Traditional Chinese Medicine Department of Postgraduate Jiangxi University of Traditional Chinese Medicine Key Laboratory of Modern Preparation of TCM Ministry of EducationJiangxi University of Traditional Chinese Medicine Collaborative Innovation Center of TCM of New Products for Geriatrics Science and Technology College Jiangxi University of Traditional Chinese Medicine

AIM To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating cd8(+)cd11c(+) cells. METHODS We evaluated the suppressive effect of Cur on cd8(+)cd11c(+) cells in spleen and Peyer's patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of cd8(+)cd11c(+) cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-gamma and transforming growth factor (TGF)-beta 1 in spleen and colonic mucosa were determined by ELISA. RESULTS The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, cd8(+)cd11c(+) cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex., cd205, cd40, cd40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-gamma and TGF-beta 1 levels were increased compared with those in mice with untreated colitis. CONCLUSION Cur can effectively treat experimental colitis, which is realized by inhibiting cd8(+)cd11c(+) cells.

关键词： cd8 cd11c Curcumin Experimental colitis Therapeutic effect

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Inverse correlation between cd8^+ inflammatory cells and E-cadherin expression in gallbladder cancer:Tissue microarray and imaging analysis

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World Journal of Clinical Cases 2017年第1期5卷 1-8页

作者： Keita Kai Masanori Masuda Shinichi Aishima Department of Pathology Saga University Hospital Department of Pathology and Microbiology Saga University Faculty of Medicine

AIM To investigated the association between the tumor cells' expression of E-cadherin and the numbers of several types of inflammatory cells infiltrating into the invasive portion of gallbladder cancer(GBC).METHODS We analyzed 50 GBC cases for which a sufficient amount of tumor tissues for tissue microarray(TMA) had been saved. Three tissue cores(3.0 mm) of invasive lesion from each case were used for the TMA. The 4-μm cut sections on slides were immunostained using primary antibodies including E-cadherin for cancer cells, leukocyte common antigen for leukocyte, myeloperoxidase for neutrophils, cd3 for T cells, cd4 for helper T cells, cd8 for killer T cells, cd20 for B cells and cd68 for macrophages. The immunostained slides were digitally analyzed by imaging analysis *** A significant inverse correlation between the number of infiltrating cd8^+ cells at invasive areas and the expression of E-cadherin by cancer cells was observed(P = 0.0001), although the degree of this correlation was relatively weak(R = 0.32). The number of cd8^+ cells and the cancer cells' E-cadherin expression were also significantly correlated with tumor differentiation(welldifferentiated vs poorly differentiated)(P = 0.0467 and P = 0.0294, respectively). Inverse correlation of T-stageand the number of cd8^+ cell infiltration was observed with statistical significance in comparison of T2 and T3 cases(P = 0.0324).CONCLUSION Our findings indicate an inverse correlation of cd8^+ T cell infiltration and cancer cells' E-cadherin expression at invasive areas of GBC. Further analyses are essential to test these findings.

关键词： E-cadherin Inflammation cd8 Gallbladder cancer Tissue microarray

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Super-resolution immunohistochemistry study on cd4 and cd8 cells and the relation to macrophages in human cochlea

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Journal of Otology 2019年第1期14卷 1-5页

作者： Wei Liu Helge Rask-Andersen Department of Surgical Sciences Section of OtolaryngologyUppsala University Hospital

Recently, the human cochlea has been shown to contain numerous resident macrophages under steady-state. The macrophages accumulate in the stria vascularis, among the auditory nerves, and are also spotted in the human organ of Corti. These macrophages may process antigens reaching the cochlea by invasion of pathogens and insertion of CI electrode. Thus, macrophages execute an innate, and possibly an adaptive immunity. Here, we describe the molecular markers cd4 and cd8 of T cells, macrophage markers MHCⅡ and cd11b, as well as the microglial markers TEME119 and P2Y12, in the human cochlea. Immunohistochemistry and the advantageous super-resolution structured illumination microscopy(SR-SIM) were used in the study. cd4^+ and cd8^+ cells were found in the human cochleae. They were seen in the modiolus in a substantial number adjacent to the vessels, in the peripheral region of the Rosenthal's canal, and occasionally in the spiral ligament. While there are a surprisingly large number of macrophages in the stria vascularis as well as between the auditory neurons,cd4^+ and cd8^+ cells are hardly seen in these areas, and neither are seen in the organ of Corti. In the modiolus,macrophages, cd4^+ and cd8^+ cells appeared often in clusters. Interaction between these different cells was easily observed with SR-SIM, showing closely placed cell bodies, and the processes from macrophages reaching out and touching the lymphocytes. Otherwise the cd4^+ and cd8^+ cells in human cochlear tissue are discretely scattered. The possible roles of these immune cells are speculated.

关键词： Macrophage Human cochlea cd4 cd8 Lymphocyte T cell

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Lineage relationship of cd8^＋ T cell subsets is revealed by progressive changes in the epigenetic landscape

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Cellular & Molecular Immunology 2016年第4期13卷 502-513页

作者： Joseph G. Crompton Manikandan Narayanan Suresh Cuddapah Rahul Roychoudhuri Yun Ji Wenjing Yang Shashank J. Patel Madhusudhanan Sukumar Douglas C. Palmer Weiqun Peng Ena Wang Francesco M. Marincola Christopher A. Klebanoff Keji Zhao John S. Tsang Luca Gatt-inoni Nicholas P. Restifo Surgery Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Cambridge Institute for Medical Research University of Cam bridge Cambridge CB20XY UK Systems Genomics and Bioinformatics Unit Laboratory of Systems Biology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD 20892 USA Department of Environmental Medicine New York University School of Medicine Tuxedo NY 10987 USA Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Department of Physics The George Washington University Washington DC 20052 USA Research Branch Sidra Medical and Research Centre Doha Qatar Infectious Disease and Immunogenetics Section Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD 20892 USA Clinical Investigator Development Program NCI/NIH Bethesda MD 20892 USA Systems Biology Center National Heart Lung and Blood Institute National Institutes of Health Bethesda MD 20892 USA. Lombardi Comprehensive Cancer Center Georgetown University Washington. DC 20007. United States. Bethesda. MD 20892. USA.

To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory cd8＋ T cells. Using a ChlP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 （H3K4me3） and H3 lysine 27 （H3K27me3） trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other cd8＋ T-cell subsets. Taken together, our results suggest that cd8＋ lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory.

关键词： T淋巴细胞干细胞基因表达记忆抗原 cd8 赖氨酸胰岛素组蛋白类

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