Investigating factors that govern T cell and dendritic cell function as therapeutic strategies for immune therapy

In 1909, Paul Ehrlich first suggested that the immune system protects against cancer. Over a century later, significant progress has been made towards understanding the interplay between the immune system and cancer, as well as many other diseases. Cancer immunotherapy is a burgeoning field of research that has great potential to complement or replace existing treatments. However, much remains to be understood in defining the precise factors that regulate immune function, particularly in the context of the complex tumor microenvironment. Dendritic cells and T cells, the prototypical immune populations involved in the generation of an adaptive, cytotoxic T cell response, play an important role in tumor immune surveillance. The activity of these immune subsets in a tumor, however, is frequently inhibited. Thus, identifying strategies to restore immune activity in the immunosuppressive tumor environment will serve to augment immune therapies for cancer. In the first part of this thesis, we show that Casitas B lymphoma b (Cbl-b), a crucial negative regulator of T cell activation, is regulated downstream of the phosphoinositol 3-kinase (PI3K)-protein kinase B/Akt (PKB) signaling pathway in T cells. Glycogen synthase kinase 3 (GSK-3), one of the first targets identified for PKB, was found to phosphorylate Cbl-b, modulating its expression. In the second part of this thesis, we clarify the role of the master cellular sensor of hypoxia, hypoxia-inducible factor 1 alpha (HIF-1Îą), in dendritic cells. HIF-1Îą plays an important role in cancer biology, but has also been shown to have opposing effects on immune function in a cell- and context-dependent manner. We found that enforced HIF-1Îą expression in bone marrow-derived dendritic cell (BMDC) cultures promotes the differentiation of myeloid-derived suppressor cells (MDSCs), an immunosuppressive population. Altogether, these data suggest two potential targets for modulating immune function and augmenting anti-tumor responses in immune therapy.Ph.D.2018-11-07 00:00:0