Impact of Host NF-kB Signaling in Radiation Therapy

PROJECT SUMMARY / ABSTRACT Investigation of cytoplasmic-to-nuclear (C?N) NF-?B signaling pathways induced by various cell surface receptors has significantly expanded the knowledge regarding the role of this transcription factor family in regulating immune/inflammatory responses and tumorigenesis.

By contrast, the physiological role of DNA damage-induced nuclear-to-cytoplasmic (N?C) NF-?B signaling remains poorly understood.

The proposed study will fill this knowledge gap by elucidating a surprising and crucial role of N?C NF-?B signaling in sustaining anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically modified mouse model that selectively disables N?C NF-?B signaling in vivo.

Our preliminary data show that radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells. We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse model.

Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained tumor regression following radiation therapy.

Based on these observations, we hypothesize that inhibition of N?C NF-?B signaling in the host improve radiation therapy via generation of tumor antigen-specific memory CD8 T cells.

We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated by inhibiting host N?C NF-?B signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of sustained tumor control mediated by inhibiting host N?C NF-?B signaling in radiation therapy (Aim 2) and target host N?C NF-?B signaling with a chemical inhibitor to improve radiation therapy (Aim 3).

The proposed study is significant because the physiological role of N?C NF-?B signaling in modulating host tumor response is completely undefined and this study will fill this knowledge gap.

It is innovative because a new mouse model and a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed.

Finally, a high impact is expected because chemical targeting of N?C NF-?B signaling by the above inhibitor may expedite timely translation to clinical trials.