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  • 1
    Keywords: TUMOR-CELLS ; carcinoma ; BREAST-CANCER ; chemotherapy ; LYMPHOCYTES ; IMMUNOTHERAPY ; immune cells ; DIFFERENTIATION ANTIGEN ; NY-BR-1 PROTEIN EXPRESSION ; ESTABLISHED MELANOMA
    Abstract: Breast cancer represents the second most common cancer type worldwide and has remained the leading cause of cancer related deaths among women. The differentiation antigen NY-BR-1 appears overexpressed in invasive mammary carcinomas compared to healthy breast tissue, thus representing a promising target antigen for T cell based tumor immunotherapy approaches. Since efficient immune attack of tumors depends on the activity of tumor antigen-specific CD4+ effector T cells, NY-BR-1 was screened for the presence of HLA-restricted CD4+ T cell epitopes that could be included in immunological treatment approaches. Upon NY-BR-1-specific DNA immunization of HLA-transgenic mice and functional ex vivo analysis, a panel of NY-BR-1-derived library peptides was determined that specifically stimulated IFNgamma secretion among splenocytes of immunized mice. Following in silico analyses, four candidate epitopes were determined which were successfully used for peptide immunization to establish NY-BR-1-specific, HLA-DRB1*0301- or HLA-DRB1*0401-restricted CD4+ T cell lines from splenocytes of peptide immunized HLA-transgenic mice. Notably, all four CD4+ T cell lines recognized human HLA-DR-matched dendritic cells (DC) pulsed with lysates of NY-BR-1 expressing human tumor cells, demonstrating natural processing of these epitopes also within the human system. Finally, CD4+ T cells specific for all four CD4+ T cell epitopes were detectable among PBMC of breast cancer patients, showing that CD4+ T cell responses against the new epitopes are not deleted nor inactivated by self-tolerance mechanisms. Our results present the first NY-BR-1-specific DRB1*0301- and HLA-DRB1*0401-restricted T cell epitopes that could be exploited for therapeutic intervention against breast cancer. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25387692
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  • 2
    Keywords: EXPRESSION ; carcinoma ; T-CELLS ; IN-SITU ; TISSUE MICROARRAYS ; TECHNOLOGY
    Abstract: OBJECTIVE: To analyze intratumoral heterogeneity of immune cells and the resulting impact of heterogeneity on the level of individual patient prediction. STUDY DESIGN: Using whole slide imaging by virtual microscopy, we present the first spatial quantitative study of immune cells in a set of colorectal cancer primary tumors. We generated "tumor maps" based on cell densities in fields of 1 mm2, visualizing intratumoral heterogeneity. In this example, cutoffs of marker-based cell stains identified by tissue microarray (TMA) led to ambiguous decisions in 11 of the 20 patients studied. Classic TMA analysis can be used in large patient cohorts to generate clinically significant predictors. The transfer of these predictors from large-scale TMA to individualized predictions thus far has not been investigated. In colorectal cancer, TMA-based quantitative immune cell counts using immune cell surface molecules (CD3, CD8, Granzyme B, and CD45RO) have been shown to be potentially better predictors for patient survival than the classical TNM system. RESULTS: Our results make clear that for individualized prognostic evaluations, whole slide imaging by virtual microscopy is irreplaceable during identification of prognostic markers as well as in their subsequent application. CONCLUSION: In the future, spatial marker signatures could contribute to individual patient classifiers.
    Type of Publication: Journal article published
    PubMed ID: 21456345
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; carcinoma ; liver ; TISSUE ; ACCUMULATION ; IFN-GAMMA ; T-CELLS ; cytokines ; DESIGN ; colorectal cancer ; COLORECTAL-CANCER ; LYMPHOCYTES ; HLA CLASS-I ; NK cells ; RECRUITMENT ; PROGNOSTIC-SIGNIFICANCE ; microenvironment ; tumor microenvironment ; CLASS-I EXPRESSION ; MUCOSAL IMMUNITY
    Abstract: Purpose: Tumor infiltrating T lymphocytes in colorectal cancer (CRC) have prognostic impact, but the role of natural killer (NK) cells in CRC tissue is unclear. The contribution of intratumoral cytokines and chemokines in shaping the composition of the inflammatory lymphocytic infiltrate is also unclear. Experimental Design: In this study, localization and densities of NK and T cells within primary CRC, CRC liver metastases, adenomas, and normal tissues were analyzed on whole tissue sections from 112 patients. In a subset of these patients, the most important 50 cytokines and chemokines were quantified in paired serum, primary CRC and adjacent mucosa samples and in CRC liver metastases and correlated with NK and T-cell infiltration, respectively. Results: The various compartments displayed characteristic differences like significantly higher chemokine concentrations in CRC tissue. Most importantly, despite high local chemokine levels, NK cells were generally scarce within CRC tumor tissues, independent of human leukocyte antigen (HLA) class I expression. Adjacent normal mucosa contained normal levels of NK cells. In contrast, corresponding T-cell numbers varied substantially and were positively correlated with higher chemokine levels. Conclusions: Our findings indicate a distinct regulation of NK cells versus T cells in the CRC tumor microenvironment. NK-cell migration into CRC tumor tissue is obviously impaired early during tumor development by mechanisms that do not affect T-cell infiltration.
    Type of Publication: Journal article published
    PubMed ID: 21325295
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