REGULATORY MECHANISMS OF INTERFERON REGULATORY FACTOR 1 IN MACROPHAGES

Abstract

Interferon regulatory factor 1 (IRF1) is a master transcription factor that bridges the innate and adaptive immune responses upon activation by invading pathogens and endogenous homeostatic cues. To investigate how these IRF1-inducing stimuli may be garnered for potential therapeutic interventions, tremendous efforts have been made but few yielded satisfactory results. This thesis examined how pathogenic signal-induced IRF1 may be exploited for therapeutic interventions through macrophages. In particular, toll-like receptor 3 (TLR3)- and TLR4-activated IRF1 were found to be specifically suppressed by the activation of TLR7, the subversion of which led to an IRF1-mediated interferon signature response that reprograms macrophage from immunosuppressive M2-like phenotype to immunostimulatory M1-like phenotype. The functional implications of IRF1-mediated responses during viral infection and tumorigenesis were further explored using in vivo mouse models and retrospective study using human patient samples. These findings provide novel insights into the therapeutic potentials of IRF1-mediated immune responses, especially during anti-tumor immunotherapy.