Publication Date

2010-06-03

Availability

Open access

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

April 2010

First Committee Member

Eli Gilboa - Committee Chair

Second Committee Member

Joseph D. Rosenblatt - Committee Member

Third Committee Member

Thomas R. Malek - Committee Member

Fourth Committee Member

Robert B. Levy - Committee Member

Fifth Committee Member

Eckhard R. Podack - Mentor

Sixth Committee Member

Marc K. Jenkins - Outside Committee Member

Abstract

Activation of immunity to self-antigens is the goal in cancer immunotherapy, whereas blocking such responses is the goal in autoimmune disease. Thus, it is not surprising that investigation into cancer immunotherapy might also produce insights for the treatment of autoimmune disease. Heat shock protein, gp96, based therapies lead to the robust activation of CD8+ cytotoxic T cells that can slow tumor growth in 60-70% of mice, but only lead to the elimination of tumors in 30-40% of animals. The primary goal of the current studies was to understand why vaccination with a secreted gp96 vaccine was not efficacious in a larger proportion of animals, and identify combination therapies that enhanced the anti-tumor activity of gp96-Ig vaccination. It was found that in mice bearing established tumors, some mice responded well to vaccination with gp96-Ig, and that the induction of CD8+ T cells was found to correlate with tumor rejection; indicating that the proportion of mice that failed to reject tumors had established mechanisms of tumor-mediated suppression of anti-tumor immunity. The mechanism of this suppression was found to differ between various tumor models, so combination therapy sought to amplify CD8+ T cell responses directly, rather than by indirectly inhibiting suppressive factors induced by established tumors. It was found that antibody-based therapies leading to the stimulation of TNFRSF25, a powerful T cell co-stimulatory receptor, caused synergistic expansion of tumor-specific T cells when given in combination with gp96-Ig vaccination and led to enhanced rejection of multiple tumor types. Interestingly, TNFRSF25 agonistic antibodies were also found to directly stimulate the proliferation of natural CD4+FoxP3+ regulatory T cells. This activity was found to be beneficial in the prevention of allergic lung inflammation when administered prior to antigen challenge. These studies have therefore identified the conditions required for successful tumor elimination following gp96-Ig vaccination, and discovered that a TNFRSF25 agonistic antibody may be used to enhance anti-tumor immunity induced by gp96-Ig. These studies have also identified TNFRSF25 stimulation as the most powerful, and physiologically relevant, method to selectively induce Treg proliferation in vivo ever discovered, with important consequences for the treatment of autoimmune inflammation.

Keywords

Regulatory T Cell; Cytotoxic T Cell; Tolerance; FoxP3; Immunosurveillance; Immunotherapy; Autoimmunity; Cancer

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