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  • 1
    Language: English
    In: Nature immunology, 2015-06, Vol.16 (6), p.609-617
    Description: Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.
    Subject(s): Animals ; Blood Vessels - immunology ; CD8-Positive T-Lymphocytes - immunology ; Cell Differentiation ; Cell Movement ; Chemotactic Factors - immunology ; Cytotoxicity, Immunologic ; Eosinophils - immunology ; Melanoma - blood supply ; Melanoma - immunology ; Melanoma, Experimental ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Neovascularization, Pathologic - immunology ; Neovascularization, Physiologic ; Skin Neoplasms - blood supply ; Skin Neoplasms - immunology ; Tumor Burden - immunology ; Tumor Microenvironment
    ISSN: 1529-2908
    E-ISSN: 1529-2916
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 2
    Language: English
    In: International journal of cancer, 2015-05-15, Vol.136 (10), p.2352-2360
    Description: Chronic inflammation is considered to be one of the hallmarks for tumor initiation and progression. Moreover, a long‐term production and accumulation of inflammatory factors lead to a local and systemic immunosuppression associated with cancer progression. However, the correlation between inflammatory mediators, immunosuppressive cells and the clinical outcome of malignant melanoma patients was poorly investigated. In this study, we performed a complex analysis of various inflammatory factors, myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the peripheral blood of patients suffering from malignant melanoma of different stages. We demonstrated that levels of serum IL‐1β, IFN‐γ and CXCL10 were significantly increased in advanced melanoma patients. In addition, these factors were found to be associated with an increased frequency of MDSCs and Tregs as compared to age‐ and gender‐matched healthy donors. Importantly, advanced melanoma patients with signs of progression displayed markedly elevated concentrations of IL‐1β and CXCL10 as compared to patients with stable disease. Moreover, an enrichment of circulating monocytic (Mo)‐MDSCs significantly correlated with a decreased progression free survival of these patients. Our data highlight a complex association between circulating inflammatory mediators, Mo‐MDSCs and the clinical outcome as well as suggest that their levels in patients with advanced melanoma are of important prognostic value allowing the identification of those with high risk of disease progression. What's new? Tumor progression can be driven by chronic inflammation that induces local and systemic immunosuppression. In this study of melanoma patients, the authors correlated circulating inflammatory factors, myeloid‐derived suppressor cells (MDSCs), and regulatory T cells (Tregs) with clinical outcome. Patients with advanced melanoma displayed an accumulation of IL‐1b, IFN‐g, CXCL10, monocytic MDSCs (Mo‐MDSCs) and Tregs. Moreover, an increase in IL‐1b, CXCL10 and Mo‐MDSCs correlated with a decreased progression free survival, indicating their important prognostic role.
    Subject(s): Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal - therapeutic use ; Cell Line, Tumor ; Chemokine CXCL10 - blood ; chronic inflammatory factors ; Disease Progression ; Female ; Humans ; immunosuppression ; Interferon-alpha - therapeutic use ; Interleukin-1beta - blood ; Ipilimumab ; Male ; melanoma ; Melanoma - blood ; Melanoma - drug therapy ; Melanoma - immunology ; Melanoma - pathology ; Middle Aged ; Myeloid Cells - immunology ; Myeloid Cells - metabolism ; Myeloid Cells - pathology ; myeloid‐derived suppressor cells ; regulatory T cells ; T-Lymphocytes, Regulatory - immunology
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Nature (London), 2014-08-21, Vol.512 (7514), p.324-327
    Description: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
    Subject(s): Animals ; Antibody Specificity ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - immunology ; Cancer ; Cancer Vaccines - immunology ; Cancer Vaccines - therapeutic use ; Care and treatment ; Development and progression ; Drug targeting ; Female ; Gene mutations ; Glioma - enzymology ; Glioma - genetics ; Glioma - immunology ; Glioma - therapy ; Gliomas ; Health aspects ; Histocompatibility Antigens Class II - immunology ; Humans ; Identification and classification ; Immune response ; Immunity, Humoral ; Immunotherapy - methods ; Isocitrate Dehydrogenase - genetics ; Isocitrate Dehydrogenase - immunology ; Male ; Mice ; Mutant Proteins - genetics ; Mutant Proteins - immunology ; Mutation ; Oncology, Experimental ; Oxidoreductases ; Research ; T-Lymphocytes, Helper-Inducer - immunology ; Xenograft Model Antitumor Assays
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Cancer immunology, immunotherapy, 2020-04, Vol.69 (4), p.677-682
    Subject(s): Autoimmune Diseases - immunology ; Autoimmune Diseases - therapy ; CAR ; Cell therapy ; Congresses as Topic ; Germany ; Humans ; Immunotherapy, Adoptive - methods ; Meeting Report ; Neoplasms - immunology ; Neoplasms - therapy ; Receptors, Antigen, T-Cell - immunology ; Regensburg center for interventional immunology (RCI) ; Synthetic immunology ; T-Lymphocytes, Regulatory - immunology ; TCR ; Treg cells
    ISSN: 0340-7004
    E-ISSN: 1432-0851
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Nature communications, 2021-02-18, Vol.12 (1), p.1119-1119
    Description: Regulatory CD4 T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4 cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation.
    Subject(s): Antigens, Neoplasm - metabolism ; Breast Neoplasms - blood ; Breast Neoplasms - genetics ; Breast Neoplasms - immunology ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Proliferation ; Clone Cells ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Immune evasion ; Immunosurveillance ; Lymphocyte Activation - immunology ; Neoplasm Staging ; Receptors, Antigen, T-Cell - immunology ; Regulatory T cells ; Single-Cell Analysis ; T-cell receptor ; T-helper 1 cells ; T-Lymphocytes, Regulatory - immunology ; Th1 Cells - immunology ; Transcriptome - genetics
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: American journal of respiratory and critical care medicine, 2018-09-15, Vol.198 (6), p.777-787
    Description: Myeloid-derived suppressor cell (MDSC) expansion has been found to play a role in disease progression in patients with cancer. However, the characteristics of MDSCs in lung cancer are poorly understood. We prospectively investigated MDSCs and inflammatory factors in tumor and peripheral blood samples from patients with resectable non-small cell lung cancer and studied their correlations with the disease prognosis. A complex analysis of MDSC subsets and inflammatory mediators was performed using flow cytometry and a Bio-Plex assay. A significant increase in the frequency of circulating monocytic (M)-MDSCs was observed in the patients with non-small cell lung cancer compared with the healthy donors (HDs). Moreover, the frequencies of M- and polymorphonuclear (PMN)-MDSCs were higher in tumors than in the peripheral blood of the same patients. This accumulation was associated with elevated concentrations of inflammatory mediators involved in MDSC migration to and activation in the tumor microenvironment. An analysis of the MDSC immunosuppressive pattern showed increased programmed death-ligand 1 expression on circulating cells from patients compared with HDs. Tumor PMN-MDSCs displayed higher programmed death-ligand 1 expression levels than the same cells in the peripheral blood. The frequency of CCR5 (C-C chemokine receptor 5) expression on circulating M-MDSCs was significantly higher in the patients than in the HDs. Clinical data analysis revealed negative correlations between recurrence-free survival and the frequencies of PMN-MDSCs and CCR5 M-MDSCs in the circulation but not in tumors. Our findings suggest that the level of MDSCs in the peripheral blood but not in tumor tissues predicts recurrence after surgery.
    Subject(s): Abridged Index Medicus ; Bone marrow ; Chemokines ; Chemotherapy ; Chronic obstructive pulmonary disease ; Disease ; Flow cytometry ; Genotype & phenotype ; Growth factors ; Ligands ; Lung cancer ; Lymphocytes ; Medical prognosis ; Melanoma ; Patients ; Tumor necrosis factor-TNF ; Tumors
    ISSN: 1073-449X
    E-ISSN: 1535-4970
    Source: ProQuest Central
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  • 7
    Language: English
    In: Cancer Immunology, Immunotherapy, 2012-03, Vol.61 (3), p.353-362
    Description: Severe immune suppression is frequent in late-stage tumor patients and promotes tumor immune evasion and subsequent tumor progression. Regulatory T cells (Treg) are major suppressors of anti-tumor immune responses. Therefore, targeting of Treg has become a key goal of anti-tumor therapy. Several preclinical and clinical observations suggest that Treg can be depleted by cyclophosphamide. Over a period of 3 months, we investigated the effect of metronomic low-dose cyclophosphamide on Treg numbers, suppressive capacity and proliferation on endogenous anti-tumor T-cell responses and on their correlation to clinical outcome in 12 patients with treatment-refractory metastasized breast cancer who received single-agent 50 mg cyclophosphamide p.o. daily. Cyclophosphamide treatment initially caused a significant reduction in circulating Treg by more than 40% (P = 0.002). However, Treg numbers completely recovered during the treatment due to increased proliferative activity and maintained their suppressive capacity. Treg depletion coincided with a strong increase in breast tumor–reactive T cells (P = 0.03) that remained at high levels during the whole period. Numbers of tumor-reactive T cells but not of Treg correlated with disease stabilization (P = 0.03) and overall survival (P = 0.027). We conclude that metronomic low-dose cyclophosphamide only transiently reduces Treg but induces stable tumor-specific T-cell responses, which correlate with improved clinical outcome in advanced-stage breast cancer patients.
    Subject(s): Adult ; Aged ; Antimitotic agents ; Antineoplastic agents ; Antineoplastic Agents, Alkylating - administration & dosage ; Antineoplastic Agents, Alkylating - therapeutic use ; Biological and medical sciences ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - immunology ; Breast Neoplasms - pathology ; Cancer ; Cancer patients ; Cancer Research ; Care and treatment ; CD4-Positive T-Lymphocytes - drug effects ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; CD8-Positive T-Lymphocytes - drug effects ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Cell Line, Tumor ; Cells ; Cyclophosphamide ; Cyclophosphamide - administration & dosage ; Cyclophosphamide - therapeutic use ; Development and progression ; Dose-Response Relationship, Drug ; Drug therapy ; Female ; Gynecology. Andrology. Obstetrics ; Humans ; Immunology ; Immunomodulation ; Immunotherapy ; Interferon-gamma - immunology ; Interferon-gamma - metabolism ; Low-dose cyclophosphamide ; Lymphocyte Count ; Mammary gland diseases ; Medical sciences ; Medicine & Public Health ; Middle Aged ; Neoplasm Metastasis ; Oncology ; Oncology, Experimental ; Patient outcomes ; Pharmacology. Drug treatments ; Regulatory T cells ; Research ; Survival Analysis ; T cells ; T-Lymphocytes, Cytotoxic - drug effects ; T-Lymphocytes, Cytotoxic - immunology ; T-Lymphocytes, Cytotoxic - metabolism ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism ; Time Factors ; Treatment Outcome ; Tumor-specific T cells ; Tumors ; U937 Cells ; Universities and colleges
    ISSN: 0340-7004
    E-ISSN: 1432-0851
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: The Journal of clinical investigation, 2015-02-01, Vol.125 (2), p.739-751
    Description: The composition of tumor-targeted T cell infiltrates is a major prognostic factor in colorectal cancer (CRC) outcome; however, the functional role of these populations in prolonging patient survival remains unclear. Here, we evaluated 190 patients with CRC for the presence of functionally active tumor-infiltrating lymphocytes (TILs), the tumor specificity of these TILs, and the correlation between patient TILs and long-term survival. Using intracytoplasmic cytokine staining in conjunction with HLA multimers loaded with tumor peptide and antigen-specific cytokine secretion assays, we determined that TNF-[alpha] expression delineates a population of tumor antigen-specific (TA-specific) cytotoxic T lymphocytes (CTLs) present within tumors from patients with CRC. Upregulation of TNF-[alpha] expression in TILs strongly correlated with an increase in the total amount of intratumoral TNF-[alpha], which is indicative of tumor-specific CTL activity. Moreover, a retrospective multivariate analysis of 102 patients with CRC, which had multiple immune parameters evaluated, revealed that increased TNF-[alpha] concentration was an independent prognostic factor. Together, these results indicate that the prognostic impact of T cell infiltrates for CRC maybe largely based on subpopulations of active TA-specific T cells within the tumor, suggesting causal implication for these cells in patient survival. Additionally, these results support the use of intratumoral TNF-[alpha], which is indicative of T cell function, as a prognostic parameter for CRC.
    Subject(s): Abridged Index Medicus ; Analysis ; Antigens ; Biomarkers ; Cloning ; Colorectal cancer ; Cytotoxicity ; Medical prognosis ; Patients ; Physiological aspects ; Prognosis ; Properties ; Software ; Studies ; Survival analysis ; T cells ; Tumors
    ISSN: 0021-9738
    E-ISSN: 1558-8238
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
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  • 9
    Language: English
    In: Cancer and metastasis reviews, 2011-03, Vol.30 (1), p.45-60
    Description: Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient.
    Subject(s): Animals ; Antigen Presentation - immunology ; Biomedicine ; Biomedicine general ; Cancer ; Cancer Research ; Chymase ; Colon cancer ; Dendritic cells ; Disease Models, Animal ; Humans ; Immune Surviellance ; Immunity, Cellular ; Mast cell ; Mast cell progenitor ; Mast Cells - immunology ; Mast Cells - pathology ; Medical colleges ; Mice ; Neoplasm Invasiveness - immunology ; Neoplasms - diagnosis ; Neoplasms - immunology ; Neoplasms - pathology ; Oncology ; Oncology, Experimental ; Polyposis ; Prognosis ; Regulatory T Cell ; Research ; T cells ; T-Lymphocytes, Regulatory - immunology ; Tryptase ; Tumor
    ISSN: 0167-7659
    E-ISSN: 1573-7233
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: Cancer Immunology Immunotherapy, 2015, Vol.64 (10), p.1271-1286
    Description: Regulatory T cell (Treg)-mediated immunosuppression is considered a major obstacle for successful cancer immunotherapy. The association between clinical outcome and Tregs is being studied extensively in clinical trials, but unfortunately, no consensus has been reached about (a) the markers and (b) the gating strategy required to define human Tregs in this context, making it difficult to draw final conclusions. Therefore, we have organized an international workshop on the detection and functional testing of Tregs with leading experts in the field, and 40 participants discussing different analyses and the importance of different markers and context in which Tregs were analyzed. This resulted in a rationally composed ranking list of “Treg markers”. Subsequently, the proposed Treg markers were tested to get insight into the overlap/differences between the most frequently used Treg definitions and their utility for Treg detection in various human tissues. Here, we conclude that the CD3, CD4, CD25, CD127, and FoxP3 markers are the minimally required markers to define human Treg cells. Staining for Ki67 and CD45RA showed to provide additional information on the activation status of Tregs. The use of markers was validated in a series of PBMC from healthy donors and cancer patients, as well as in tumor-draining lymph nodes and freshly isolated tumors. In conclusion, we propose an essential marker set comprising antibodies to CD3, CD4, CD25, CD127, Foxp3, Ki67, and CD45RA and a corresponding robust gating strategy for the context-dependent analysis of Tregs by flow cytometry.
    Subject(s): Animals ; Antigens, CD - metabolism ; Biomarkers - metabolism ; Cancer Research ; Cell Separation ; Cells ; Cells, Cultured ; Consensus ; Female ; Flow Cytometry ; Forkhead Transcription Factors - metabolism ; Humans ; Immunology ; Immunotherapy ; International Cooperation ; Ki-67 Antigen - metabolism ; Lymphocyte Activation ; Medicine & Public Health ; Monitoring ; Monitoring, Immunologic ; Oncology ; Original ; Ovarian Neoplasms - immunology ; Phenotyping ; Reference Standards ; T cells ; T-Lymphocytes, Regulatory - immunology ; Tregs ; Tumor Escape
    ISSN: 0340-7004
    E-ISSN: 1432-0851
    Source: Alma/SFX Local Collection
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