Dept. of Molecular Microbiology and Immunology
Oregon Health & Science University
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-Î² (TGF-Î²) 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-Î² signaling inhibits Î±OX40 mediated anti-tumor therapy in a pre-clinical mouse cancer model. In chapter 3, we found that while Î±OX40 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-Î² receptor inhibitor (SM16). Evaluation of tumor infiltrating T cells showed that Î±OX40/SM16 dual therapy resulted in an increase in proliferating granzyme B expressing CD8[superscript +] T cells which were better able to produce IFNÎ³. These results show that combining Î±OX40 with TGF-Î² inhibitors is potentially a promising cancer immunotherapy that hopefully will be tested in future clinical trials.
School of Medicine
Triplett, Todd Ashley, "Identification of a novel human CD4[superscript +] T cell population and overcoming the immunosuppressive environment in large established tumors" (2012). Scholar Archive. 785.