Degree Granting Department
Biology (Cell Biology, Microbiology, Molecular Biology)
Amer A. Beg
adenovirus, immunity, inflammation, lung cancer, vaccine
Nuclear factor-κB (NF-κB) is one of the main regulators of inflammatory and immune responses. It is a family of transcription factors composed of five members: RelA, RelB, cRel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). Homo- and hetero-dimers of family members are inhibited by inhibitor of &klappaB (IκB) family members and activated by IκB kinase (IKK) family members. The IKK family is comprised of IKKα, IKKΒ, and IKKγ. The focus of my dissertation delves into the role of NF-κB activation by IKKΒ in both an immunotherapy setting and its role in T cell mediated anti-tumor immune responses.
A central focus of immunotherapy is to develop vaccine adjuvants that are capable of enhancing a protective adaptive immune response. Microbial adjuvants in vaccines activate key transcription factors, including NF-κB and interferon response factors (IRF). The individual role of these transcription factors in successful vaccines is not clear. We used constitutively active IKKΒ (CA-IKKΒ) expressed in an adenoviral vector (AdIKK) to determine the role of classical NF-κB activation in a vaccine-induced immune response. In an in vivo model, AdIKK induced rapid and sustained NF-κB-driven inflammation in the lungs compared to the control virus. AdIKK infection had no impact on the magnitude of T cell activation as measured by IFN-γ production; however pulmonary inflammation resulted in increased cellularity of draining lymph nodes (LN) at early timepoints resulting in increased early antibody and T cell responses. Taken together, these findings show that IKKΒ-induced NF-κB activation of an inflammatory response affects the kinetics, but not the magnitude of the adaptive immune response.
NF-κB is activated in many tumor types and contributes to the progression of cancer by suppressing apoptosis, and enhancing proliferation, angiogenesis and metastasis. NF-κB is also activated in other cells within the tumor microenvironment and promotes inflammation initiated by neutrophils and macrophages. In addition to inflammatory cells, T cells can be found within the tumor microenvironment and are associated with improved patient survival. Using CA-IKKΒ, we sought to determine if NF-κB activation in tumor cells could promote T cell mediated tumor immunity. In both primary tumors and a metastatic tumor model, we found that NF-κB expression in tumors rendered immunogenic through expression of Kb-OVA led to tumor rejection or growth suppression. Tumor regression was mediated by increased CD8 T cell recruitment by chemokines. Microarray results showed increases in T cell chemokines, including CCL2 and CCL5. Knock-down of CCL2 by Lentiviral shRNA in LLC-OVA-IKK cells resulted in abrogation of tumor regression. These results suggest that NF-κB is capable of promoting immune surveillance in tumors through increased recruitment of T cells.
Overall, my dissertation highlights beneficial roles of IKKΒ-induced activation of NF-κB in two separate systems: vaccine induced immune responses and tumor immune surveillance.
Scholar Commons Citation
Hopewell, Emily, "Enhancing the immune response through IKKbeta-induced activation of NF-kappaB" (2012). Graduate Theses and Dissertations.