Interferon Regulatory Factor 3 in Interferon Gamma Receptor Signaling and Cancer Immunology

Every year millions of people die from cancer throughout the world, and tens of millions of people are diagnosed with cancer worldwide. When surgery is not an option, treatment options commonly rely on the host immune system for optimal treatment efficacy. The expression of Interferon gamma (IFN-γ) by host immune cells is often associated with favorable antitumor immune responses. How IFN-γ is optimally induced in immune cells, and how IFN-γ promotes the transcription of genes downstream of the Interferon gamma receptor (IFNGR) is incompletely understood. Understanding how to induce immune cells to express optimal IFN-γ, and how the IFNGR induces optimal expression of genes could help in understanding how to effectively treat and eliminate cancer in patients. The research described in this dissertation describes how the transcription factor interferon regulatory factor 3 (IRF3) is essential for optimal expression of IFN-γ in response to tumor challenge. Additionally, these studies also describe an essential role for IRF3 for gene expression downstream of the IFNGR. Finally, this research describes how IFN-γ can reduce tumor cell viability, and how this viability can be further reduced through co-stimulation with the toll-like receptor 3 (TLR3) agonist polyinosinic-polycytidylic acid (Poly I:C), and how these effects rely on IRF3. Altogether, these results indicate that IRF3 is essential for optimal immune responses towards tumor challenge, and for optimal expression of anti-tumoral genes in tumor cells responding to IFN-γ stimulation.Advisors: Thomas M. Petro and Audrey Aiken