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      Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses

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          Abstract

          Background:

          Some cancer patients are immuno-compromised, and it has been long felt that immune-intervention is not compatible with standard chemotherapies. However, increasing evidence suggests that standard chemotherapy drugs may stimulate beneficial changes in both the immune system and tumour.

          Methods:

          We have assessed the expression of human leucocyte antigen class 1 (HLA1) on tumour cells before and after chemotherapy agents (cyclophosphamide, oxaliplatin or gemcitabine). In addition, we show that chemotherapy-stressed tumour cells may release cytokines that enhance the interactions between dendritic cells (DCs) and T cells into growth media.

          Results:

          Here we report that some chemotherapy agents can increase HLA1 expression in tumour cells, even when expression is low. Increases were associated with killing by cytotoxic T cells, which were negated by HLA1-blockade. Furthermore, T-cell function, as indicated by increased proliferation, was enhanced as supernatants derived from tumours treated with chemotherapy augmented DC-maturation and function.

          Conclusion:

          There is evidence that a facet of immune surveillance can be restored by appropriate chemotherapy agents. Also, tumours exposed to some chemotherapy may secrete cytokines that can mature DCs, which ultimately enhances T-cell responses.

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          Most cited references39

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          Taking dendritic cells into medicine.

          Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.
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            Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution.

            Since its introduction in 1994 (J. Immunol. Methods 171 (1994) 131), the flow cytometric analysis of lymphocyte proliferation by serial halving of the fluorescence intensity of the vital dye CFSE (carboxyfluorescein diacetate, succinimidyl ester or CFDA-SE) has become widely used in immunological laboratories around the world. This technique allows the visualisation of eight to 10 discrete cycles of cell division by flow cytometry, both in vitro and in vivo. Appropriately conjugated antibodies can be used to probe surface marker changes as cells divide, or changes in expression of internal molecules such as cytokines when appropriate fixation and permeabilisation protocols are used. An added advantage of the technique is the ability to recover viable cells which have undergone defined numbers of cell divisions by flow cytometric sorting, allowing functional studies to be performed. Other commonly used assays of cell proliferation give only limited information, as they usually measure division at a population level. The CFSE technique can be used to determine kinetics of immune responses, track proliferation in minor subsets of cells and follow the acquisition of differentiation markers or internal proteins linked to cell division.
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              Chronic immune activation and inflammation as the cause of malignancy

              Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers. © 2001 Cancer Research Campaign http://www.bjcancer.com
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                08 December 2009
                05 January 2010
                05 January 2010
                : 102
                : 1
                : 115-123
                Affiliations
                [1 ]Section of Oncology, Division of Cellular and Molecular Medicine, St George's University of London London, UK
                Author notes
                [* ]Author for correspondence: w.liu@ 123456sgul.ac.uk
                Article
                6605465
                10.1038/sj.bjc.6605465
                2813751
                19997099
                6be77cc7-c4d3-431e-abfa-fcdf8f2ae191
                Copyright 2010, Cancer Research UK
                History
                : 23 October 2009
                : 03 November 2009
                : 06 November 2009
                Categories
                Translational Therapeutics

                Oncology & Radiotherapy
                hla1,chemotherapy,dendritic cells,immunovisibility,immunotherapy
                Oncology & Radiotherapy
                hla1, chemotherapy, dendritic cells, immunovisibility, immunotherapy

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