Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response ...to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune(suppressive)status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.
Abstract Ovarian cancer is a devastating disease with a high relapse rate. Due to a mostly asymptomatic early stage and lack of early diagnostic tools, the disease is usually diagnosed in a late ...stage. Surgery and chemotherapy with taxanes and platinum compounds are very effective in reducing tumor burden. However, relapses occur frequently and there is a lack of credible second-line options. Therefore, new treatment modalities are eagerly awaited. The presence and influx of immune cells in the ovarian cancer tumor microenvironment are correlated with survival. High numbers of infiltrating T cells correlate with improved progression free and overall survival, while the presence of regulatory T cells and expression of T cell inhibitory molecules is correlated with a poor prognosis. These data indicate that immunotherapy, especially cell-based immunotherapy could be a promising novel addition to the treatment of ovarian cancer. Here, we review the available data on the immune contexture surrounding ovarian cancer and discuss novel strategies and targets for immunotherapy in ovarian cancer. In the end the addition of immunotherapy to existing therapeutic options could lead to a great improvement in the outcome of ovarian cancer, especially when targeting cancer stem cells.
Abstract Background Considering the high mortality rate of ovarian cancer due to the absence of curative treatment in advanced stage or at recurrence, new therapeutic strategies are urgently needed. ...Immunotherapy is one of these strategies that yielded promising results in fundamental and animal research in the past years. However, implementation in clinical practice remains poor. The aim of this review is to gain insight into the mechanisms of interaction between ovarian cancer and the immune system in order to develop better immunotherapeutic strategies. Methods We searched the published literature for studies focusing on interactions between ovarian cancer and the immune system, with emphasis on outcome data in order to create a knowledge base that is well grounded in clinical reality. Results The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Besides the immune-activating tumor infiltrating lymphocytes (TILs), immune-suppressive regulatory T-cells (Tregs), tolerance-inducing plasmacytoid dendritic cells (pDCs), B7-H4+ macrophages, immune-suppressive cytokines such as IL10 and TGF-β are also found in the tumor environment. Myeloid-derived suppressive cells (MDSCs) are recently found to have a significant role in immune suppression in ovarian cancer in murine studies. Furthermore, vascular endothelial growth factor (VEGF) is also known to have an immune-suppressing role besides its angiogenic role. All those concerted mechanisms result in the creation of an environment where the cancer is invincible and can grow unhampered. Conclusion Further knowledge of the mechanisms involved is needed to develop better strategies and improve the clinical applicability of immunotherapy. Effective immunotherapy must combine immune-activating strategies with elimination of immune-suppressing mechanisms. We believe that tilting the balance from an immune-suppressive to an immune-active environment may have an enormous impact on the disease.
The objective of this study was to characterize fibroblasts at sequential time points during intra‐oral wound healing in the rat. Experimental wounds were made at several time points in the ...mucoperiosteum of the palate of 35‐day‐old Wistar rats. Fibroblasts were cultured from the biopsies under standard conditions for the same number of passages. The expression of the integrin subunits α1, α6, and β1; and the intermediate filaments α‐smooth muscle actin and vimentin were analyzed by flow cytometry. Western blot analysis was performed at 0, 8, and 60 days postwounding to confirm the expression of both intermediate filaments. The phenotypic profiles of fibroblasts cultured from subsequent stages in the wound healing process differed considerably. We conclude that distinct fibroblast phenotypes can be isolated from different stages in wound healing. These phenotypes remained stable during in vitro culturing. In addition, cryosections of the wound areas were made at identical time points and were immunohistochemically stained for the same antigens. The immunohistochemical staining correlated well to the flow‐cytometric data. These results suggest the occurrence of multiple subpopulations of fibroblasts with a specialized function during wound healing. We hypothesize that undesirable consequences of wound healing might be prevented through the modulation of specific fibroblast subpopulations. (WOUND REP REG 2003;11:55–63)
The fungal pathogen Candida albicans has a multilayered cell wall composed of an outer layer of proteins glycosylated with N- or O-linked mannosyl residues and an inner skeletal layer of beta-glucans ...and chitin. We demonstrate that cytokine production by human mononuclear cells or murine macrophages was markedly reduced when stimulated by C. albicans mutants defective in mannosylation. Recognition of mannosyl residues was mediated by mannose receptor binding to N-linked mannosyl residues and by TLR4 binding to O-linked mannosyl residues. Residual cytokine production was mediated by recognition of beta-glucan by the dectin-1/TLR2 receptor complex. C. albicans mutants with a cell wall defective in mannosyl residues were less virulent in experimental disseminated candidiasis and elicited reduced cytokine production in vivo. We concluded that recognition of C. albicans by monocytes/macrophages is mediated by 3 recognition systems of differing importance, each of which senses specific layers of the C. albicans cell wall.
In the late stages of muscle development, a unique cell population emerges that is a key player in postnatal muscle growth and muscle regeneration. The location of these cells next to the muscle ...fibers triggers their designation as satellite cells. During the healing of injured muscle tissue, satellite cells are capable of forming completely new muscle fibers or restoring damaged muscle fibers. A major problem in muscle healing is the formation of dysfunctional scar tissue, which leads to incomplete functional recovery. Therefore, the identification of factors that improve the process of muscle healing and reduce the formation of scar tissue is of great interest. Because satellite cells possess the capability of self-renewal, a unique feature of stem cells, they play a central role in the search for therapies to improve muscle healing. Growth factor-based and (satellite) cell-based therapies are being investigated to treat minor muscle injuries and intrinsic muscle defects. Major muscle injury that involves the loss of muscle tissue requires the use of scaffolds with or without (satellite) cells. Scaffolds are also being developed to generate muscle tissue in vitro. These approaches aim to restore the structure and function of the injured muscle without dysfunctional scarring.
Dendritic cells (DCs) are professional antigen presenting cells, well equipped to initiate an immune response. For effective induction of an immune response, DC should migrate from the periphery to ...the lymph node to present the antigen to T lymphocytes. Currently, tumor-antigen loaded DCs are used in clinical vaccination trials in cancer patients. To investigate the migratory capacity of DC in vivo, a variety of fluorescent and radioactive labels have been used. Here we introduce a novel tool to study DC migration in vivo: DCs generated from enhanced green fluorescent protein (EGFP)-transgenic mice. DC from EGFP-transgenic mice display typical DC behavior and can be matured without affecting their autofluorescence in vitro. In addition, the continuously produced cytoplasmic EGFP in living cells functions as a viability marker, since EGFP released from dying cells does not stain DC from C57Bl/6 mice upon coculture. In vivo migration studies using EGFP-DC and indium-111-labeled DC were performed to determine the efficiency of i.d. versus s.c. administered DC to reach the draining lymph node. The analysis demonstrates that i.d. injection increases the amount of EGFP-DC/indium-111-labeled DC in the lymph node compared to s.c. injection. Subsequent quantitative, phenotypical and ultrastuctural analysis demonstrate that DC generated from EGFP-transgenic mice are well suited to study the migratory behavior, distribution and phenotype of DC in vivo.
CC chemokine ligand 18/dendritic cell‐chemokine 1 (CCL18/DC‐CK1) is a CC chemokine, preferentially expressed by DC, which acts as a chemoattractant for naive T cells and mantle zone B cells. Applying ...a newly developed CCL18/DC‐CK1 sandwich enzyme‐linked immunosorbent assay, we demonstrate that DC secrete high amounts of CCL18/DC‐CK1 and that this expression can be increased by interleukin‐10. High levels of CCL18/DC‐CK1 were also detected in human serum (average of 88 ng/ml). Moreover, elevated CCL18/DC‐CK1 levels were detected in synovial fluid from rheumatoid arthritis patients and in drain fluid (average of 254 ng/ml and 122 ng/ml, respectively). Immunoprecipitation experiment using anti‐CCL18/DC‐CK1 monoclonal antibodies revealed a protein of 6–7 kDa in serum and drain fluid that was indistinguishable from recombinant CCL18/DC‐CK1 on Western blot and in re‐aggregation assays. The concentration of CCL18/DC‐CK1 found in human serum is in the same order of magnitude as was previously reported to completely inhibit CCL11/eotaxin‐induced CC chemokine receptor 3 (CCR3) activation and consequent migration of eosinophils. CCL18/DC‐CK1 may therefore function as an agonist (for naive T and B cells) and as an antagonist for CCR3‐expressing leukocytes such as eosinophils.
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