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    Human mesothelioma induces defects in dendritic cell numbers and antigen processing function which predict survival outcomes

    Access Status
    Open access via publisher
    Authors
    Cornwall, S.
    Wikstrom, M.
    Musk, A.
    Alvarez, J.
    Nowak, A.
    Nelson, Delia
    Date
    2015
    Type
    Journal Article
    
    Metadata
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    Citation
    Cornwall, S. and Wikstrom, M. and Musk, A. and Alvarez, J. and Nowak, A. and Nelson, D. 2015. Human mesothelioma induces defects in dendritic cell numbers and antigen processing function which predict survival outcomes. OncoImmunology. 31 Aug 2015: pp. 1-12.
    Source Title
    OncoImmunology
    DOI
    10.1080/2162402X.2015.1082028
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/18165
    Collection
    • Curtin Research Publications
    Abstract

    AbstractMesothelioma is an almost invariably fatal tumor with chemotherapy extending survival by a few months. One immunotherapeutic strategy is to target dendritic cells (DCs), key antigen presenting cells involved in antigen presentation, to induce antigen-specific T cell responses. However, DC-targeting will only be effective if DCs are fit-for-purpose, and the functional status of DCs in mesothelioma patients was not clear. We found that mesothelioma patients have significantly decreased numbers of circulating myeloid (m)DC1 cells, mDC2 cells and plasmacytoid (p)DCs relative to healthy age and gender-matched controls. Blood monocytes from patients could not differentiate into immature monocyte-derived DCs (MoDCs), indicated by a significantly reduced ability to process antigen and reduced expression of costimulatory (CD40, CD80 and CD86) and MHC (HLA-DR) molecules, relative to controls. Activation of mesothelioma-derived MoDCs with LPS+/?IFN? generated partially mature MoDCs, evident by limited up-regulation of the maturation marker, CD83, and the costimulatory markers. Attempts to rescue mesothelioma-derived DC function using CD40Ligand(L) also failed, indicated by maintenance of antigen processing capacity and limited up-regulation of CD40, CD83, CD86 and HLA-DR. These data suggest that mesothelioma patients have significant numerical and functional DC defects and that their reduced capacity to process antigen and reduced expression of costimulatory molecules could induce anergized/tolerized T cells. Nonetheless, survival analyses revealed that individuals with mesothelioma and higher than median levels of mDC1s and/or whose MoDCs matured in response to LPS, IFN? or CD40L lived longer, implying their selection for DC-targeting therapy could be promising especially if combined with another treatment modality.

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