Date of Award

January 2012

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard L. Edelson

Subject Area(s)

Immunology

Abstract

DENDRITIC CELLS AS SOLID TUMOR IMMUNOTHERAPY: UTILIZING NATURAL DEFENSES TO STRIVE TO ERADICATE CANCER.

Anna K. Engberg, Carole L. Berger, Douglas J. Hanlon, Robert E. Tiglaar, and Richard L. Edelson. Department of Dermatology, Yale University, School of Medicine, New Haven, CT.

Extracorporeal photochemotherapy (ECP) is a widely used immunotherapy for advanced cutaneous T-cell lymphoma (CTCL). ECP's capacity to expand CD8+ T-cell populations with specificity for CTCL cells, as well as to generate large scale rapid maturation of

monocytes into functional dendritic antigen presenting cells (DC), suggests that the treatment may also be applicable to immunotherapy of solid tumors. To test this premise, we assessed ECP's capacity to efficiently stimulate in vitro anti-melanoma T-cell

responses. Our experimental system permitted us to analyze the contributions of individual variables, including a modified plastic flow plate and biodegradable nanoparticles. Induced DC were pulsed with the melanoma associated antigens gp100 and Melan-A/Mart-1. DC were then co-cultured with autologous CD8+ cells. After 10 days, the T cells were then exposed to antigen-specific target cells, and supernatant was analyzed for IFN-gamma; production. Using dextramer staining, we were able to show that plate-passed DC expand antigen specific T cells. These T cells are able to recognize target cells and release IFN-gamma;, confirming their functionality. These results reveal that the maturationally synchronized DC that are induced on a large scale by ECP, in a single day without added cytokines, can stimulate vigorous anti-melanoma CD8+ T-cell responses. ECP-induced DC therefore offer an attractive source of antigen presenting cells for potential anti-melanoma immunotherapy trials.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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