https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/29010
type: CreativeWork
name: Blocking Immunosuppressive Factors and Taking Advantage of the Nutrient Supply Within the Tumor Microenvironment: Pathways to Achieve Improved Cancer Immunotherapeutic Efficacy for Patients With Metastatic Melanoma
description: The incidence of melanoma is increasing. Immunotherapy commonly fails due to the immunosuppressive tumor microenvironment (TME). The aim of my dissertation is to develop strategies that dampen the TME’s immunosuppressive capacity and improve the antitumor performance of vaccine-induced melanoma-associated antigen (MAA)-specific CD8+T cells. I pursued this goal using three approaches. First, interactions between co-inhibitors on CD8+ tumor-infiltrating lymphocytes (TILs) with immunoinhibitory ligands within the TME impair T cells’ effector functions. I assessed whether blocking immunoinhibitory signaling during T cell priming augments their antitumor activity. I designed a melanoma vaccine expressing MAAs within herpes simplex virus (HSV) glycoprotein D (gD), which blocks the inhibitory BTLA/CD160-HVEM pathway. Compared to a non-gD vaccine, the gD-adjuvanted vaccine enhances CD8+T cells to low avidity epitopes and prolongs survival of tumor-bearing mice. gD renders MAA-specific CD8+TILs more resistant to functional impairment within TME, which increases their ability to limit tumor progression. Second, the stroma of solid tumors is crucial for tumorigenesis and suppresses the CD8+TILs’ effector functions. To determine whether destroying tumor stroma could improve the MAA-specific CD8+T cells’ tumoricidal capacity, I designed a vaccine targeting the fibroblast activation protein (FAP), which is expressed at high levels on tumor-stromal fibroblasts. Combining the vaccines to FAP and MAAs significantly improves the survival of tumor-bearing mice. This is caused by destruction of FAP+ cells, which reduces frequencies and inhibitory functions of immunosuppressive cells. It also decreases the MAA-specific CD8+TILs’ metabolic stress and delays their progression towards functional exhaustion. Finally, the TME commonly lacks nutrients and oxygen needed for the CD8+TILs’ energy production. My data demonstrate that these metabolic challenges profoundly contribute to the CD8+TIL…
abstract: The incidence of melanoma is increasing. Immunotherapy commonly fails due to the immunosuppressive tumor microenvironment (TME). The aim of my dissertation is to develop strategies that dampen the TME’s immunosuppressive capacity and improve the antitumor performance of vaccine-induced melanoma-associated antigen (MAA)-specific CD8+T cells. I pursued this goal using three approaches. First, interactions between co-inhibitors on CD8+ tumor-infiltrating lymphocytes (TILs) with immunoinhibitory ligands within the TME impair T cells’ effector functions. I assessed whether blocking immunoinhibitory signaling during T cell priming augments their antitumor activity. I designed a melanoma vaccine expressing MAAs within herpes simplex virus (HSV) glycoprotein D (gD), which blocks the inhibitory BTLA/CD160-HVEM pathway. Compared to a non-gD vaccine, the gD-adjuvanted vaccine enhances CD8+T cells to low avidity epitopes and prolongs survival of tumor-bearing mice. gD renders MAA-specific CD8+TILs more resistant to functional impairment within TME, which increases their ability to limit tumor progression. Second, the stroma of solid tumors is crucial for tumorigenesis and suppresses the CD8+TILs’ effector functions. To determine whether destroying tumor stroma could improve the MAA-specific CD8+T cells’ tumoricidal capacity, I designed a vaccine targeting the fibroblast activation protein (FAP), which is expressed at high levels on tumor-stromal fibroblasts. Combining the vaccines to FAP and MAAs significantly improves the survival of tumor-bearing mice. This is caused by destruction of FAP+ cells, which reduces frequencies and inhibitory functions of immunosuppressive cells. It also decreases the MAA-specific CD8+TILs’ metabolic stress and delays their progression towards functional exhaustion. Finally, the TME commonly lacks nutrients and oxygen needed for the CD8+TILs’ energy production. My data demonstrate that these metabolic challenges profoundly contribute to the CD8+TIL…
author: Zhang, Ying Zhang
language: en
date published: 2016-01-01
date modified: 2026-07-24T03:45:38Z
provider: University of Pennsylvania
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Pennsylvania