Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Jose R. Conejo-Garcia

Abstract

Through rational drug design, much progress has been made to develop small molecules that specifically inhibit the oncogenic signaling pathways driving malignant growth. However, the normal function of immune cells depends upon many of the same pathways inhibited by such targeted cancer therapies. Because the immune system can influence the growth of many cancers, I hypothesized that most small molecule inhibitors would have activity on leukocytes relevant in cancer, and this activity would contribute to their antitumor mechanisms. In order to test this hypothesis, I first screened a panel of over 40 small molecule inhibitors for their activity on proliferating human cancer cells and human T cells. Almost every small molecule inhibitor I tested had detrimental activity on human T cells at the concentrations required for limiting tumor cell proliferation. However, when I focused on the FDA approved MEK inhibitor trametinib, I found that some common γ-chain cytokines were able to rescue T-cell functions blunted by trametinib. Notably, an IL-15 agonist, ALT-803, could rescue the in vivo proliferation of tumor-antigen specific T cells in mice treated with trametinib. I developed a p53-/-KrasG12D+Myristoylated-p110α+ murine breast cancer model to perform tumor challenge experiments in a model only weakly sensitive to trametinib, a setting where combination with immunotherapy may be clinically useful. In this tumor model, ALT-803 synergized with trametinib, even leading to tumor rejection in several mice. Trametinib treatment alone was able to limit tumor growth, but this activity actually depended upon the presence of CD8+ T cells. Upon further investigation I found that trametinib reduced the expansion of monocytic myeloid-derived suppressor cells (MDSCs) in tumor-bearing mice, a finding also recapitulated in vitro during the expansion of MDSCs from mouse and human bone marrow. These results suggest the inhibitory activity of trametinib on T cells in vivo is overcome by a corresponding reduction in immunosuppressive MDSCs and the endogenous presence of common γ-chain cytokines, and that the function of antitumor T cells can be further enhanced by IL-15 agonists administered during trametinib therapy. This work also demonstrates the importance of considering immune-dependent mechanisms of targeted therapies when designing personalized cancer treatments.

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