Inflammation mediated by the transcription factor NFkB is a hallmark of many cancers. Toll-like receptor (TLR) signaling activates NFkB and many tumors undergo an upregulation of TLR expression. However, it still remains unknown to what extent TLR signaling directly contributes to tumorigenesis. A mutagenesis screen of the Unc93b1 protein, a trafficking factor for endosomal TLRs, identified numerous gain-of-function mutations that lead to enhanced TLR signaling. This system allows me to selectively upregulate the activity of certain TLRs and test their contribution to the development of spontaneous inflammation and cancer. So far, my work has focused on a group of Unc93b1 mutations that confer hyper-responsiveness of TLR7 and TLR9, two endosomal nucleic-acid sensing receptors. Knock-in mice carrying this mutation show an early onset of autoinflammation and autoimmunity, demonstrating the critical role of Unc93b1 in maintaining immunological tolerance of these receptors. In ongoing work, I want to investigate the underlying molecular mechanisms that mediate this TLR hyperresponse and identify new regulators of Unc93b1 that might engage in this pathway. Furthermore, I want to apply this system in exploring the contribution of chronic TLR7 and TLR9 stimulation in the development of B-cell lymphoma, a cancer type whose pathogenesis relies on constitutively active NFkB downstream of TLR engagement. My study will reveal novel regulatory pathways that control TLR-mediated inflammation and their physiological relevance in tumorigenesis.
Citation Format: Olivia Majer, Bo Liu, Angus Yiu-fai Lee, Greg Barton. Dysregulated Toll-like receptor responses as an oncogenic driver [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B130.
- ©2016 American Association for Cancer Research.