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    Developing Therapies to Overcome Immunosuppressive Myeloid Cells in the Tumor Microenvironment

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    Author
    Ceradoy, Justine Anne
    Advisor
    Davila, Eduardo, Ph.D.
    Date
    2018
    Type
    dissertation
    
    Metadata
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    Abstract
    Myeloid cells in the tumor microenvironment represent significant barriers to the development of successful cancer immunotherapies. A multi-kinase inhibitor, Regorafenib (Reg), and a DNA-PK inhibitor, NU7441 (NU) were shown in a previous study to reduce expression of immunoinhibitory proteins in adaptive immune cells while increasing stimulatory MHC-I on cancer cells. In this study, we explored whether these drugs could reverse the suppressive activity of myeloid-derived suppressor cells (MDSCs) and alternatively activated macrophages. To test this idea, we used splenocytes from tumor-bearing mice and a human monocytic cell line differentiated into suppressive macrophages and assessed Arginase activity, their ability to suppress effector T cells, and mRNA expression of immunosuppressive and activating markers. We showed that Reg/NU decrease arginase activity and increase immunoactivating markers. These data demonstrate that treatment of suppressive myeloid cells with Reg/NU confers a less suppressive phenotype and leads to the generation of a more activating phenotype.
    Description
    2018
    Molecular Medicine
    University of Maryland, Baltimore
    M.S.
    Keyword
    Oncology
    Immunology
    cancer targeted therapy
    M2 macrophage
    MDSC
    tumor microenvironment
    Cancer--Immunotherapy
    Tumors--Immunological aspects
    Molecular Targeted Therapy
    Myeloid-Derived Suppressor Cells
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/9008
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