Date

June 2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

T cell proliferation, survival and effector function are tightly regulated by the presence of cytokines and expression of their receptors. Interleukin-2 (IL-2) was the first cytokine discovered and studies have shown that IL-2 availability and IL-2 receptor (CD25) expression promotes T cell activation, proliferation and survival. CD25 expression by murine T cells is primarily restricted to CD4[superscript +]Foxp3[superscript POS] Tregs. In contrast, it has been reported that a large proportion of CD4[superscript +]FOXP3[superscript NEG] non-Tregs express low-intermediate levels of CD25 in humans. This CD25[superscript LO/INT]FOXP3[superscript NEG] population of human T cells was originally thought to represent recently activated cells, however this T cell population had not been studied in depth. Given the current practice of targeting the IL-2 signaling pathway in the clinic, we sought to fully characterize this population. In chapter 2, we show that contrary to what has been reported in the literature, these cells are not recently activated but represent a quiescent memory subpopulation. Our analyses found that this CD25[superscript INT] population was phenotypically and functionally distinct from the CD25[superscript NEG] memory CD4[superscript +] T cells in vitro and was differentially affected in vivo by IL-2 treatment in cancer patients. We and others have not been able to find a mouse equivalent for this population, therefore studies performed in mice regarding the role of IL-2/CD25 may not necessarily translate to humans. Hence, these findings improve our understanding of the role of CD25 in human immunology and may also have clinical implications by helping to illuminate the mechanisms and potentially improve the efficacy of therapies that target IL-2 and CD25. In contrast to IL-2, transforming growth factor-β (TGF-β) has been shown to negatively influence T cell proliferation and effector function and is known to inhibit anti-tumor T cell responses, especially in large established tumors. Therefore, we sought to determine whether TGF-β signaling inhibits αOX40 mediated anti-tumor therapy in a pre-clinical mouse cancer model. In chapter 3, we found that while αOX40 therapy alone was ineffective at treating large established tumors, it was able to elicit complete regression in ~85% of the mice when given in conjunction with a TGF-β receptor inhibitor (SM16). Evaluation of tumor infiltrating T cells showed that αOX40/SM16 dual therapy resulted in an increase in proliferating granzyme B expressing CD8[superscript +] T cells which were better able to produce IFNγ. These results show that combining αOX40 with TGF-β inhibitors is potentially a promising cancer immunotherapy that hopefully will be tested in future clinical trials.

Identifier

doi:10.6083/M4K0729M

School

School of Medicine

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