Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Until about 1990 there was general consent about the assumption that only protein and peptide antigens have the capacity of CD4(+) or CD8(+) T-cell stimulation. Since about ten years evidence is now accumulating that carbohydrate-peptide epitopes do play a role in classical MHC-mediated immune responses. This holds true for glycopeptides, where the glycan chain is short and not located at an "anchor residue" needed for MHC interaction. T-cell recognition of O-glycosylated peptides is potentially of high biomedical significance, because it can mediate the immune protection against microorganisms, the vaccination in anti-tumor therapies, but also some aspects of autoimmunity. The epithelial type 1 transmembrane mucin MUC1 is established as a marker for monitoring recurrence of breast cancer and is a promising target for immunotherapeutic strategies to treat cancer by active specific immunization. Natural human immune responses to the tumor-associated glycoforms of the mucin indicate that antibody reactivities are more directed to glycopeptide than to non-glycosylated peptide epitopes. To overcome the weak immunogenicity of the natural target, heavily O-glycosylated MUC1, the question was addressed whether O-linked glycans remain intact during processing in the MHC class II pathway and interfere with endosomal processing and peptide presentation. Attempts were made to define on a biochemical level the structural requirements for an efficient endosomal proteolysis catalyzed by cathepsin L in antigen-presenting cells. Evidence based on work with CD4(+) T-hybridomas confirms that O-glycopeptides can be effectively presented to T-cells and that glycans can form integral parts of the TCR defined epitopes. Similar approaches are currently followed in the MHC class I pathway which aim at the identification of immunogenic glycopeptides generated by immunoproteasomes.
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PMID:Immunology of O-glycosylated proteins: approaches to the design of a MUC1 glycopeptide-based tumor vaccine. 1691 45

Cryoablation of cancer leaves tumor-associated antigens intact in an inflammatory microenvironment that can stimulate a regional anti-tumor immune response. We examined whether cryoablated tumor draining lymph nodes (CTDLN) as adoptive immunotherapy may be an effective immunotherapeutic approach in the adjuvant treatment of breast cancer. BALB/c mice with MT-901 mammary adenocarcinoma tumors underwent cryoablation, resection or no treatment and tumor draining lymph nodes were harvested. Cryoablation resulted in only a mild increase in the absolute number of T-cells but a significant increase in the fraction of tumor-specific T-cells as evidenced on IFN-gamma release assay. FACS analysis demonstrated no significant relative shift in the proportion of CD4(+) or CD8(+) cells. The adoptive transfer of CTDLN resulted in a significant reduction of pulmonary metastases as compared to TDLN from either tumor-bearing mice or mice who underwent surgical excision. Cryoablation prior to surgical resection of breast cancer can be used as a method to generate effector T-cells for adjuvant adoptive cellular immunotherapy.
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PMID:Adoptive immunotherapy of breast cancer with lymph node cells primed by cryoablation of the primary tumor. 1697 45

CD8 T cell-mediated immune responses fall into two distinct types based on effector cell-derived cytokine production. Type I CD8 T cells (Tc1) produce IFN-gamma, whereas type 2 cells (Tc2) secrete IL-4, IL-5, IL-10, and GM-CSF. Using a murine TCR transgenic T cell/breast tumor model, we show that adoptively transferred Ag-specific Tc1 cells are more effective in delaying mammary tumor growth and progression than that of functionally distinct Tc2 cells. Donor Tc1 cells administered 7 days posttumor challenge localized and persisted at sites of primary tumor growth with antitumor responses that were dependent, in part, on effector cell-derived IFN-gamma. Tc1-mediated responses markedly enhanced the appearance and local accumulation of highly differentiated (CD44(high)) CD4 and CD8 endogenous tumor-infiltrating T cells when compared with that of untreated tumor-bearing mice. Conversely, Tc1 cell transfer markedly delayed the appearance of corresponding nondifferentiated (CD44(low)) endogenous T cells. Such cells were acutely activated as defined by coexpression of surface markers associated with TCR engagement (CD69) and early T cell activation (CD25). Moreover, cellular response kinetics appeared to further correlate with the up-regulation of endogenous T cells producing the chemokine IFN-gamma-inducible protein-10 in vivo. This suggested that CD8-mediated type 1 antitumor responses cannot only promote accumulation of distinct endogenous CD4 and CD8 T cell subpopulations, but also facilitate and preferentially modulate their localization kinetics, persistence, states of activation/differentiation, and function within the primary tumor environment at various stages of tumor progression. These studies offer insight into potential mechanisms for enhancing T cell-based immunotherapy in breast cancer.
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PMID:CD8-mediated type 1 antitumor responses selectively modulate endogenous differentiated and nondifferentiated T cell localization, activation, and function in progressive breast cancer. 1711 96

Antigenic differences between normal and malignant cells of the cancer patient form the rationale for clinical immunotherapeutic strategies. Because the antigenic phenotype of neoplastic cells varies widely among different cells within the same malignant cell-population, immunization with a vaccine that stimulates immunity to the broad array of tumor antigens expressed by the cancer cells is likely to be more efficacious than immunization with a vaccine for a single antigen. A vaccine prepared by transfer of DNA from the tumor into a highly immunogenic cell line can encompass the array of tumor antigens that characterize the patient's neoplasm. Poorly immunogenic tumor antigens, characteristic of malignant cells, can become strongly antigenic if they are expressed by highly immunogenic cells. A DNA-based vaccine was prepared by transfer of genomic DNA from a breast cancer that arose spontaneously in a C3H/He mouse into a highly immunogenic mouse fibroblast cell line, where genes specifying tumor-antigens were expressed. The fibroblasts were modified in advance of DNA-transfer to secrete an immune augmenting cytokine and to express allogeneic MHC class I-determinants. In an animal model of breast cancer metastatic to the brain, introduction of the vaccine directly into the tumor bed stimulated a systemic cellular anti-tumor immune response measured by two independent in vitro assays and prolonged the lives of the tumor-bearing mice. Furthermore, using antibodies against the various T-cell subsets, it was determined that the systemic cellular anti-tumor immunity was mediated by CD8(+), CD4(+) and NK/LAK cells. The application of DNA-based genomic vaccines for the treatment of a variety of brain tumors is being explored.
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PMID:Antigenic Differences Between Normal and Malignant Cells as a Basis for Treatment of Intracerebral Neoplasms Using a DNA-Based Vaccine. 1716 Jan 40

Immunotherapy in cancer relies on the identification and characterization of potential target antigens that can be recognized by effector cells of the immune system. Several strategies have been developed to identify such antigens, which then can be used for immunization strategies. Serological analysis of recombinant tumor cDN expression libraries (SEREX) identifies tumor antigens based on a spontaneous humoral immune response in cancer patients. SEREX is not limited to tumor types that can be grown in cell culture nor does it depend on T-cell clones that recognize the autologous tumor. SEREX-defined antigens need to be evaluated following an algorithm of several analytical steps before they become new target antigens for active immunotherapy: expression analysis to evaluate tumor association, serological analysis with sera from tumor patients and normal individuals to prove tumor-associated immunogenicity, identification of potential peptide epitopes for CD8 and CD4 T-cells, and evaluation in T-cell assays to demonstrate their potential use as vaccine targets. We recently identified a new breast cancer differentiation antigen designated as NY-BR-1 in an autologous breast cancer SEREX screening. The different steps of further evaluation are summarized in this chapter.
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PMID:Potential target antigens for immunotherapy identified by serological expression cloning (SEREX). 1717 36

We have reported that fusions of patient-derived dendritic cells (DC) and autologous breast cancer cells induce T-cell responses against autologous tumors. However, the preparation of fusion cells requires patient-derived tumor cells, and these are not always available in the clinical setting. In the present study, we explore an alternative approach to constructing DC-breast cancer fusion vaccine by using breast cancer-cell lines. DC generated from HLA-A*0201-positive donor were fused to HLA-A*0201+ allogeneic MCF7 breast cancer cells. These fusion cells co-expressed tumor-associated antigens and DC-derived costimulatory and MHC molecules. Both CD4 and CD8 T cells were activated by the fusion cells as demonstrated by the production of IFN-gamma. The fusion cells induced strong antigen-specific cytotoxic T lymphocytes (CTL) activity against their parent cells. The lysis of targets was restricted by HLA-A*0201, since killing was blocked by the anti-HLA-A2 mAb. Similar CTL activity against HLA-A*0201-positive targets was induced when T cells were cocultured with fusions of DC and HLA-A*0201-negative allogeneic BT20 breast cancer cells. In addition, administration of T cells stimulated by DC-breast cancer fusion cells regressed 7-day-old tumors and rendered mice free of disease up to 90 days. These results suggest that tumor-cell lines can be used as a fusion partner in the construction of DC-tumor fusion vaccine. Such fusion cells hold promise since they can be used as a vaccine for active immunotherapy or as stimulators to activate and expand T cells for adoptive immunotherapy.
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PMID:Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells. 1723 4

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.
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PMID:Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. 1729 84

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417-1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4(+) T cells. We now show that CD4(+) T cells infiltrating breast cancer tumors secrete type 1 (interferon gamma) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4(+) T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid beta2 microglobulin-deficient mice engrafted with human CD34(+) hematopoietic progenitor cells and autologous T cells. There, CD4(+) T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development.
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PMID:Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. 1743 63

Different immune effectors control distinct steps in tumor metastasis; T cells inhibit the growth of primary and metastatic tumors, while NK control tumor cells in transit. Vaccination with DNA encoding Her-2 which is expressed on primary and metastasized breast cancer cells induced both humoral and cellular immunity to inhibit tumor growth. Vaccination efficacy can be amplified by depleting CD4;+CD25;+Foxp3;+ regulatory T cells (Treg), but the risk of inducing autoimmunity warrants new strategies to selectively amplify anti-tumor immunity when modulating Treg. In the tumors, the major cyclooxygenase (COX)-2 product is prostaglandin E2(PGE2) which suppresses T and NK cells while amplifying Treg. These cellular responses to PGE2 are mediated through four E prostanoid (EP) receptors. Cox inhibitors and EP antagonists enhance NK activity to inhibit tumor metastasis; but they may down regulate MHC class I expression. Since T and NK cells have opposite requirements for MHC class I expression, their relative contribution to cancer control may vary with the stage of the disease. To enhance tumor infiltration by immune effectors, the role of CXCL9 is discussed. The complex nature of tumor metastasis necessitates a comprehensive approach to achieve successful immune intervention.
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PMID:Prospects of controlling breast cancer metastasis by immune intervention. 1747 70

Of 1416 HIV-infected patients seen at Ramathibodi Hospital over a 5-year period (1999-2003), 42 were diagnosed with malignancies, giving a prevalence of 3%. Twenty-one of these patients (50%) were men and their mean age was 40.8 years. The median CD4 cell count was 235 cells/muL. AIDS-related malignancies were found in 26 patients (62%). The most common AIDS-related malignancies were non-Hodgkin's lymphoma (NHL) (33%), cervical cancer (21%) and Kaposi's sarcoma (KS) (5%). Breast cancer was the most common non-AIDS-related malignancy (10%). Eleven patients (26%) died. The 75% survival time of patients who received treatment for their malignancy was longer than that of patients who received no treatment (18.3 vs 1.2 months; P<0.01).
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PMID:Malignancies in HIV-infected Thai patients. 1756 79


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