All ETDs from UAB

Advisory Committee Chair

Richard D Lopez

Advisory Committee Members

Kevin W Harris

Zdenek Hel

Christopher A Klug

Ralph D Sanderson

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Unlike antigen-specific alpha beta-T cells, gamma delta-T cells can recognize and lyse cancerous cells rapidly upon encounter in a manner that does not require the recognition of tumor-specific antigens. Given the well-documented capacity of gamma delta-T cells to innately kill malignant cells, efforts are now underway to exploit the antitumor properties of gamma delta-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of gamma delta-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively-transferred gamma delta-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled gamma delta-T cells, we show that adoptively-transferred syngeneic gamma delta-T cells localize to breast tumors in a mouse model of breast cancer. Moreover, in both syngeneic and xenogeneic models of breast cancer, we demonstrate that adoptively-transferred gamma delta-T cells are both effective against breast cancer and are well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively-transferred gamma delta-T cells for the treatment of breast cancer. Additionally, we investigated a critical issue surrounding gamma delta-T cell cancer immunotherapy, which relates to the findings that only in some cancer patients is it possible to activate and/or expand gamma delta-T cells either in vivo or ex vivo regardless of the methodology employed. This is in stark contrast to what is observed in healthy individuals, as gamma delta-T cells reliably respond to proliferative stimuli. To investigate this issue, we attempted the expansion of gamma delta-T cells from tumor-bearing mice, instead of healthy mice (as performed in the studies mentioned above) for the adoptive-transfer into tumor-bearing hosts. We found that gamma delta-T cells in tumor-bearing mice were numerically rare and expanded poorly ex vivo and that tumor cells were responsible for this numerical and functional exhaustion of gamma delta-T cells. Using both in vitro and in vivo models of different cancers we demonstrate that gamma delta-T cells undergo apoptosis after encounter with tumor cells and we identified several putative genes involved in this exhaustion of gamma delta-T cells. These findings will facilitate the development of the next generation of clinical trials exploiting the tumor-reactive properties of gamma delta-T cells.

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