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    Enhancing Anti-Cancer Properties of Human Natural Killer Cells

    Cover for Enhancing Anti-Cancer Properties of Human Natural Killer Cells
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    View/Open: Fitzgerald_georgetown_0076D_14827.pdf (8.4MB) Bookview
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    Creator
    Fitzgerald, Allison
    Advisor
    Weiner, Louis M
    ORCID
    0000-0002-2814-0481
    Abstract
    Immunotherapy has revolutionized cancer treatment. Certain immunotherapies, such as immune checkpoint inhibitors and CAR-T cell therapy, provide long lasting remissions. Unfortunately, the majority of tumors are unresponsive to immunotherapy and tumors that initially respond frequently develop resistance. In order to improve patient clinical outcomes a greater understanding of anti-tumor immunology is required to broaden and refine immunotherapy treatment. While there are two types of cytotoxic lymphocytes that kill malignant cells, CD8+ T cells and natural killer (NK) cells, NK cells are under-studied in comparison to CD8+ T cells. In this dissertation, I explore multiple ways to enhance NK cell anti-cancer properties.
     
    In cancer, patients with high tumoral NK cell content and activation have improved survival and response to immunotherapy. Because of this, NK cells are emerging as major targets to promote cancer immunotherapy. Current NK-focused immunotherapy approaches include autologous or allogenic NK cell transfer, CAR-NK cells, NK immune checkpoint inhibitors, bi- or tri-specific killer engagers (BiKEs and TriKES), and cytokine super-agonists. An impediment to all these therapies is inadequate NK cell honing to and/or infiltration into solid tumors. The first part of this dissertation describes approaches to enhance NK cell tumor honing and infiltration, either through pharmacologic means or by genetic engineering. Specifically, I detail 1) that NK cells express fibroblast activation protein (FAP) which regulates NK cell tumor infiltration (chapters 1, 2, 4 and 5) and 2) how a dipeptidyl peptidase inhibitor, which inhibits FAP and other members of the dipeptidyl peptidase family, enhances NK cell tumor infiltration and increases anti-PD-1 efficacy (chapter 3).
     
    Once NK cells enter the tumor milieu, they can become exhausted, limiting their anti-tumor potential. NK cell exhaustion is marked by upregulation of immune checkpoints. While PD-1 and CTLA-4 are immune checkpoints expressed by exhausted T cells, their expression and functionality in NK cells is controversial. In chapter 6, I demonstrate human NK cells express CTLA-4 and suggest anti-CTLA-4 immune checkpoint therapy may restore NK cell function leading to tumoral NK cell activation.
     
    In sum, this dissertation describes multiple novel approaches to altering NK cell biology to enhance their anti-tumor activity and potentially improve patient outcomes.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1062385
    Date Published
    2021
    Subject
    Cellular Migration; Immunology; Immunotherapy; Natural Killer Cells; Pancreatic Cancer; Oncology; Immunology; Cytology; Oncology; Immunology; Cellular biology;
    Type
    thesis
    Embargo Lift Date
    2022-08-12
    Publisher
    Georgetown University
    Extent
    314 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
    Metadata
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    Georgetown University Seal
    ©2009 - 2023 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility