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    Identifying Molecular Determinants of Immune Rejection in Pancreatic Cancer

    Cover for Identifying Molecular Determinants of Immune Rejection in Pancreatic Cancer
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    View/Open: Ajina_georgetown_0076D_14476.pdf (4.9MB) Bookview

    Creator
    Ajina, Reham S
    Advisor
    Weiner, Louis M
    Abstract
    Worldwide, nearly half a million people are diagnosed with pancreatic cancer every year, with mortality rates of more than 90%. Pancreatic cancer has unique biological features. It is characterized by atypical neoplastic glands surrounded by dense collagenous stroma. Pancreatic cancer stroma accounts for more than 50% of the total tumor mass, and it is highly immunosuppressive. Although many attempts have been made to overcome the pancreatic cancer immunosuppressive microenvironment, the vast majority of clinical studies have failed. In order to improve pancreatic cancer patients’ clinical outcomes, we need to deeply understand the complex immunosuppressive biology of this disease. The goal of this study was to address the extent to which immune evasion in pancreatic cancer is a tumor-intrinsic property and if it is induced in response to immune selection pressure. To address this goal, mT3-2D murine pancreatic cancer cells were inoculated subcutaneously into immunocompetent wild-type (WT) and severe combined immunodeficiency (SCID) syngeneic mice, and the effects of immune selection pressure on mT3-2D tumors were evaluated. Two types of analysis were performed: (i) whole tumor analysis and (ii) malignant epithelial cell analysis. The former determines the effect of immune selection pressure on the tumor environment, including cancer cells and non-cancer stromal elements, whereas the latter determines how malignant cells specifically respond to immune selection pressure. I determined that although T cell immunity is induced in immunocompetent tumors, T cell anti-tumor immunity incompletely regulates tumor growth. Further analysis revealed that in response to immune selection pressure, malignant epithelial pancreatic cancer cells stimulate the recruitment and mimicry of myeloid cells. These immunosuppressive mechanisms are potentially induced via the upregulation of the Signal Transducer and Activator of Transcription (STAT) 1. In fact, based on the Cancer Genome Atlas survival analysis, STAT1 is a significant unfavorable prognostic factor in human pancreatic cancer. Targeting the STAT pathway using the FDA-approved drug, ruxolitinib, in combination with a programmed cell death inhibitor (anti-PD1) results in the downregulation of myeloid associated genes and improves survival in mice. Future studies will explore the mechanisms by which the STAT1 transcription factor regulates the expression of myeloid traits in pancreatic cancer cells.
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1059674
    Date Published
    2020
    Subject
    immunogenicity; Immunosuppression; Immunotherapy; Pancreatic Cancer; PDAC; T cell immunity; Biology; Biology;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    184 leaves
    Collections
    • Graduate Theses and Dissertations - Tumor Biology
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility