# Tumor cell-intrinsic STING signaling and IFN-Beta gene regulation in cancer

> **NIH NIH F30** · UNIVERSITY OF CHICAGO · 2022 · $51,752

## Abstract

Patients with evidence of spontaneous anti-tumor T cell responses have a better prognosis and are likely to
respond to checkpoint blockade immunotherapies currently used in the clinic. Identifying why some patients
lack spontaneous anti-tumor immune responses and finding ways to promote endogenous responses will likely
expand efficacy to these patients. Our lab has previously shown immunogenic tumors spontaneously activate
the innate immune system through the STING pathway. The STING pathway senses cytosolic DNA, which
activates a signal transduction pathway culminating in nuclear translocation of transcription factors IRF3 and
NF-κB that, in turn, induce expression of several genes including IFN-β. STING signaling and IFN-β receptor
signaling in tumor-infiltrating immune cells are both required for optimal priming of CD8+ T cells against tumor
antigens. Likewise, intratumoral injection of STING agonists increases IFN-β expression, anti-tumor T cell
priming, and causes dramatic tumor rejection in pre-clinical models. As part of our work with intratumoral
STING agonists we observed that the tumor cells themselves were the only cell type present in the tumor
microenvironment unable to express IFN-β in response to cytosolic DNA or direct STING agonists. We tested a
range of tumor cell lines and found the vast majority was unable to express IFN-β downstream of STING
signaling, arguing that loss of activation of this pathway might occur regularly as a component of oncogenesis.
Our over-arching hypothesis is that determining why tumor cells lack IFN-β expression and reversing this
phenotype could lead to a new strategy to induce endogenous anti-tumor immune responses. Our preliminary
data indicates that STING signaling is largely in tact in tumor cells up to and including nuclear translocation of
IRF3. We find tumor cells have a defect in IRF3 DNA binding at the IFN-β locus and that the lack of IFN-β
expression following STING activation is a dominant phenotype. To better understand tumor cell-intrinsic
STING signaling, and how it is defective in tumor cells, we propose to: 1) identify and reverse the molecular
mechanism preventing STING induction of IFN-β in tumor cells using pre-clinical models where we can
observe how this affects the tumor/immune interface in vivo 2) understand the potential for STING signaling in
human cancer by analyzing both cell lines and tumor biopsies. Preliminary data suggests tumor cells differ
from control cells in the epigenetic accessibility of the IFN locus and NF-κB signaling after STING activation.
Therefore we will study NF-kB signaling in tumor cells and it's affect on accessibility of the IFN locus. We will
also silence the STING pathway in the few tumor cells capable of expressing IFN-β to observe how this
modulates the interface with host immunity. As we analyze human tumor cell lines and biopsies we will begin
to determine what fraction of patients might respond to therapies designed to enable tumor cells to exp...

## Key facts

- **NIH application ID:** 10421324
- **Project number:** 5F30CA232379-05
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Blake Flood
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10421324

## Citation

> US National Institutes of Health, RePORTER application 10421324, Tumor cell-intrinsic STING signaling and IFN-Beta gene regulation in cancer (5F30CA232379-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10421324. Licensed CC0.

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