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  • 1
    Keywords: CANCER ; EXPRESSION ; IN-VIVO ; GENERATION ; DISEASE ; SITE ; TISSUE ; RESPONSES ; SKIN ; ASSOCIATION ; bone marrow ; BONE-MARROW ; breast cancer ; LYMPHOCYTES ; IMMUNITY ; INTERFERON-ALPHA ; AUTOIMMUNITY ; DISORDERS ; LUPUS-ERYTHEMATOSUS ; REACTIVE T-CELLS ; TUMOR BIOLOGY ; anti-tumor ; T-cell immunity
    Abstract: A wide variety of cancer types has been associated with paraneoplastic autoimmune disorders and with the induction of autoimmunity against several autoantigens, among them self-antigens that are also expressed by tumor cells. This raises the question of autoimmune disorders as a result of immune reactions to the tumor. To date, however, requirements for the generation of autoimmune reactions in cancer patients remain largely unclear. In this study, we characterized conditions in altogether 131 patients, which determine autoimmune responses in primary breast cancer patients. We used ex vivo IFN-gamma EliSpot assays against autologous tumor or skin lysates to evaluate tumor- and auto-reactive T-cells (TCs) in the bone marrow (BM) as well as ELISA, ECLIA, and turbidimetric immunoassays for the detection of auto-reactive antibodies in the peripheral blood and compared results to intratumoral cytokine concentrations and pathobiological features of the primary tumor tissue. We here demonstrate a significant correlation between anti-tumor BMTC responses and cellular autoimmune reactivity in primary breast cancer patients (P = 0.002). Humoral autoimmune reactions, however, were negatively correlated with anti-tumor TC immunity (P = 0.039). We observed auto-reactive BMTCs especially in patients with well-differentiated, hormone receptor-positive carcinomas (P = 0.009). Furthermore, elevated concentrations of intratumoral IFN-alpha significantly correlated with the induction of cellular autoimmune reactivity (P = 0.0002), while humoral autoimmune reactions correlated with increased levels of intratumoral IL-12 (P = 0.04). Altogether, these data indicate a significant role of the tumor microenvironment and particularly that of IFN-alpha and IL-12 in the induction of systemic autoimmune responses and imply that the primary tumor tissue represents an integral site of autoimmune regulation in cancer patients
    Type of Publication: Journal article published
    PubMed ID: 21161218
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  • 2
    Keywords: PEPTIDE ; EXPRESSION ; AUTOIMMUNE-DISEASE ; BONE-MARROW ; IDENTIFICATION ; STRATEGIES ; CANCER PATIENTS ; INTERLEUKIN (IL)-2 ; MAMMAGLOBIN
    Abstract: Regulatory T cells (Tregs) play an important role in controlling antitumor T-cell responses and hence represent a considerable obstacle for cancer immunotherapy. The abundance of specific Treg populations in cancer patients has been poorly analyzed so far. Here, we demonstrate that in breast cancer patients, Tregs often control spontaneous effector memory T-cell responses against mammaglobin, a common breast tissue-associated antigen that is overexpressed by breast carcinoma. Using functional assays, we identified a HLA-DRB1*04:01- and HLA-DRB1*07:01-restricted epitope of mammaglobin (mam(34-48)) that was frequently recognized by Tregs isolated from breast cancer patients. Using mam(34-48)-labeled HLA Class II tetramers, we quantified mammaglobin-specific Tregs and CD4(+) conventional T (Tcon) cells in breast carcinoma patients as well as in healthy individuals. Both mammaglobin-specific Tregs and Tcon cells were expanded in breast cancer patients, each constituting approximately 0.2% of their respective cell subpopulations. Conversely, mammaglobin-specific Tregs and CD4(+) Tcon cells were rare in healthy individuals (0.07%). Thus, we provide here for the first time evidence supporting the expansion of breast tissue-specific Tregs and CD4(+) Tcon cells in breast cancer patients. In addition, we substantiate the potential implications of breast tissue-specific Tregs in the suppression of antitumor immune responses in breast cancer patients. The HLA Class II tetramers used in this study may constitute a valuable tool to elucidate the role of antigen-specific Tregs in breast cancer immunity and to monitor breast cancer-specific CD4(+) T cells.
    Type of Publication: Journal article published
    PubMed ID: 23894725
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  • 3
    Keywords: PEPTIDE ; ANGIOGENESIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; INVASION ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; GENERATION ; TISSUE ; PATIENT ; RESPONSES ; IFN-GAMMA ; ANTIGEN ; FLOW ; BONE-MARROW ; BREAST ; breast cancer ; BREAST-CANCER ; IMMUNE-RESPONSES ; MEMORY ; IDENTIFICATION ; METASTASIS ; LYMPHOCYTES ; CANCER-CELLS ; PEPTIDES ; CANCER-PATIENTS ; IMMUNE-RESPONSE ; T-LYMPHOCYTES ; CELL-SURFACE ; CANCER PATIENTS ; TUMOR CELLS ; TOLL-LIKE RECEPTORS ; INCREASED EXPRESSION ; RE ; PANCREATIC-CANCER ; BASEMENT-MEMBRANE ; secretion ; TUMOR-CELL ; MAMMALIAN HEPARANASE ; PEOPLE ; CANDIDATE ; ANTITUMOR ; SULFATE PROTEOGLYCANS
    Abstract: Increased expression and secretion of heparanase (Hpa) by tumor cells promotes tumor invasion through extracellular matrices, tissue destruction, angiogenesis, and metastasis. Here, we show the existence in breast cancer patients of Hpa-specific T lymphocytes by fluorescence-activated cell sorting flow cytometry using Hpa peptide-MHC class I tetramers. We furthermore show memory T-cell responses in a high proportion of breast cancer patients to Hpa-derived HLA-A2-restricted peptides, leading to production of IFN-gamma and to generation of antitumor CTLs lysing breast cancer cells. Such CTLs recognized endogenously processed respective Hpa peptides on Hpa-transfected and Hpa-expressing untransfected breast carcinoma cells. According to these results and to the fact that such cells were not found in healthy people, Hpa seems to be an attractive new tumor-associated antigen and its HLA-A2-restricted peptides ought to be good candidates for peptide vaccination to reactivate memory immune responses to invasive and metastatic cancer cells
    Type of Publication: Journal article published
    PubMed ID: 16885374
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; proliferation ; BLOOD ; carcinoma ; CELL ; Germany ; DISEASE ; TISSUE ; MICE ; ANTIGEN ; AUTOIMMUNE-DISEASE ; T-CELL ; T-CELLS ; bone marrow ; BONE-MARROW ; cytokines ; IN-SITU ; CANCER-PATIENTS ; CARCINOMAS ; INVOLVEMENT ; INTERFERON ; FLOW-CYTOMETRY ; pancreatic carcinoma ; chronic pancreatitis ; inflammation ; CYTOKINE ; PANCREATIC-CANCER ; PHASE ; regulatory T cells ; LYMPHOCYTE SUBSETS ; SCLEROSING PANCREATITIS
    Abstract: BACKGROUND & AIMS: Chronic pancreatitis is characterized by alternating phases of acute inflammation and quiescent disease. Involvement of T-cell responses has been suggested, but pancreatitis-specific T cells have not been described. METHODS: We characterized T-cell responses against pancreatitis, pancreatic carcinoma-associated antigens, and tetanus toxoid in the bone marrow, blood, and/or pancreatitis lesions of patients with pancreatitis, pancreatic cancer, and healthy individuals. T cells were functionally characterized by antigen-dependent secretion of interferon (IFN)-gamma, interleukin (Il)-4, and IL-10, which indicate type 1, type 2, or regulatory T-cell responses, respectively. Regulatory T cells were characterized by multicolor flow cytometry. Isolated regulatory T cells were tested for their capacity to recognize pancreatitis-associated antigens and to suppress conventional T cells in an antigen-dependent manner. T cell-derived cytokines in tissue lesions were quantified by enzyme-linked immunosorbent assay. RESULTS: Chronic pancreatitis patients showed similar to pancreatic cancer patients and healthy individuals type 1 T-cell responses against tetanus toxoid; however, they exhibited strong IL-10-based T-cell responses against pancreatitis-associated but not pancreatic carcinoma-associated antigens. T cells from pancreatic cancer patients responded to pancreatic cancer-associated but not pancreatitis-associated antigens with IFN-gamma secretion. Pancreatitis-specific IL-10 responses were mediated by IL-10(+)IFN-gamma(-)FoxP3(+) regulatory T cells, which were expanded in the blood, bone marrow, and pancreatitis lesions and possessed the potential to suppress the proliferation of autologous conventional T cells in an antigen-specific manner. Pancreatitis lesions, in comparison with pancreatic carcinomas, contained increased concentrations of IL-10 and reduced levels of IFN-gamma, suggesting pancreatitis-specific activity of regulatory T cells in situ. CONCLUSIONS: Chronic pancreatitis is associated with disease-specific regulatory T-cell responses
    Type of Publication: Journal article published
    PubMed ID: 19931255
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