The advent of immune checkpoint inhibitors has transformed the clinical management of metastatic melanoma. These monoclonal antibodies, targeted against CTLA-4 and PD-1, have shown durable and long-lasting responses in a subset of melanoma patients. However, response rates remain incomplete, even when using combination therapy (CTLA-4 plus PD-1). Identifying predictive or controlling features of responsiveness has been an urgent goal in oncology research. Our group and others have previously shown responding tumors display high levels of E-cadherin, a cell-cell adhesion molecule which defines an epithelial-like phenotype. The goal of this work is to define the significance of E-cadherin in the context of checkpoint blockade. Here, a novel B16F10 melanoma mouse model is presented in which E-cadherin is exogenously expressed (B16.E-cad). The parental B16F10 line does not express E-cadherin and is poorly immunogenic and notoriously resistant to treatment with immune checkpoint inhibitors. Thus, B16.E-cad and the vector control model epithelial-like (responsive) and mesenchymal-like (non-responsive) phenotypes respectively. I find, compared to vector control, B16.E-cad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo, despite similar proliferation rates in vitro. Analysis of immune cell infiltration (FACS) performed on tumors grown in C57/BL6 mice revealed no differences between B16.Vector, B16.Ecad and the immunogenic control, B16.SIY. Conversely, transplantation of B16.E-cad into Rag1-/-mice abrogated tumor growth delay indicating an immune-mediated tumor response. Additionally, B16.Ead tumors displayed greater responses to combination checkpoint inhibitor therapy. Overall, the results of this dissertation indicate an epithelial-like phenotype in melanoma tumors facilitates tumor immunosurveillance and responsiveness to immune checkpoint blockade, which has broad prognostic and therapeutic implications.
|Advisor:||Tackett, Alan J.|
|Commitee:||Hutchins, Laura, Mahmoud, Fade, Shalin, Sara, Wong, Henry|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Cancer, Immunotherapy, Melanoma, Proteomics|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be