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Overcoming dendritic cell-mediated suppression of T cell responses in a prostate tumor environment

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dc.contributor.advisor Jianzhu Chen and K. Dane Wittrup. en_US Higham, Eileen M en_US
dc.contributor.other Massachusetts Institute of Technology. Dept. of Biological Engineering. en_US 2011-02-23T14:34:17Z 2011-02-23T14:34:17Z 2010 en_US 2010 en_US
dc.description Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2010. en_US
dc.description Cataloged from PDF version of thesis. en_US
dc.description Includes bibliographical references. en_US
dc.description.abstract Prostate cancer is the most prevalent malignancy in American men, leading to significant mortality each year. This is in part due to a lack of effective treatments for advanced disease. The prostate is considered an ideal organ for cancer immunotherapy, because it is both nonessential and expresses several prostate-specific antigens than could be targeted for an immuno- therapeutic response. However, such therapy is limited by the tolerization of CD8⁺ T cells in tumors, rapidly abrogating anti-tumor responses. In order to better understand the factors necessary to induce, maintain and promote productive T cell responses against cancer, this research has focused on understanding and interrupting critical interactions between CD8⁺ T cells and immunosuppressive networks within tumors. As our model system, we explored CD8⁺ T cell recognition of spontaneous prostate cancer in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. We demonstrated that both naive and effector tumor-reactive T cells are rapidly tolerized in the prostates and prostate draining lymph nodes (PDLN) of TRAMP mice, and that dendritic cells are important factors driving their tolerization. We then developed two novel immuno- therapeutic approaches to locally overcome the suppressive influence of dendritic cells. In one approach, we engineered tumor-reactive T cells to express the immunostimulatory protein CD40 ligand to mature dendritic cells in the PDLN. This work demonstrated for the first time that tumor-reactive T cells could be engineered to deliver stimulatory signals to dendritic cells in tumor environments to enhance the function of adoptively transferred T cells. In a second approach, we injected ex vivo matured, antigen-loaded dendritic cells into tumors to overcome the influence of endogenous suppressive dendritic cells. This work demonstrated for the first time that intratumoral injections of dendritic cells into spontaneous primary tumors could significantly delay the tolerization of tumor-infiltrating effector T cells and reverse the tolerization of resident tumor-infiltrating lymphocytes (TILs), generating new potential therapeutic applications for TILs. These two approaches establish that mechanism-based immuno- therapeutic interventions can be rationally designed to locally interrupt immunosuppressive networks within tumors. As the TILs enhanced through this work are representative of those found in cancer patients, such approaches could have significant clinical impact. en_US
dc.description.statementofresponsibility by Eileen M. Higham. en_US
dc.format.extent 184 p. en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. en_US
dc.rights.uri en_US
dc.subject Biological Engineering. en_US
dc.title Overcoming dendritic cell-mediated suppression of T cell responses in a prostate tumor environment en_US
dc.type Thesis en_US Ph.D. en_US
dc.contributor.department Massachusetts Institute of Technology. Dept. of Biological Engineering. en_US
dc.identifier.oclc 701718712 en_US

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