# Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2023 · $408,425

## Abstract

PROJECT SUMMARY – PROJECT 4
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is now one of the most deadly malignant diseases.
Aging is a high-risk factor for HCC development, although the underlying mechanisms are poorly understood.
The aging liver is characterized by progressive development of an immunosuppressive microenvironment,
contributed by chronic interferon (IFN) signaling, metabolic changes and altered innate and adaptive immunity.
Thus, liver tumors are poorly responsive to immunotherapy. The goal of project 4 is to elucidate the roles of IFN
and other inflammatory cytokines in aging-related changes of the hepatic immunological landscape. This project
was prompted by our unexpected finding in most recent experiments. In dissecting molecular mechanisms of
liver tumorigenesis with an inducible gene targeting system, Mx1-cre, we identified a robust tumor-inhibitory
effect of polyinosinic-polycytidylic acid (polyIC), a synthetic dsRNA that induces IFN expression. These data on
IFN signaling not only challenge a widely known theory of IL1a-IL6 cytokine circuit in liver tumorigenesis, but
also open up new strategies for HCC immunotherapy. However, preliminary data also showed that injecting
polyIC into aged mice triggered sharply different immune responses and actually aggravated HCC progression
if given at late tumor stages. Thus, we hypothesize that IFN and other related inflammatory cytokines have
bidirectional or paradoxical roles in HCC development, depending on ages and tumor stages. To test this
hypothesis, we will extensively interrogate the roles of IFN signaling in a NASH-HCC model at single cell
resolution. We will also further develop and optimize a math model and a TI (tumorigenic index) calculation
system to quantitatively measure tumorigenic signal strength, tumor stages and prognosis, and also evaluate
tumor-inhibitory effects of various manipulation or treatment strategies. Of note, preliminary data also showed
robust induction of PD-L1 expression by polyIC in the liver, which prompted us to test a combination of polyIC
and PD-L1/PD-1 blockade in treatment of liver cancer in young and old mice. We shall extensively investigate
how coordinated activation of innate and adaptive immune functions can effectively suppress primary and
metastatic tumor progression in the liver. Finally, we shall take advantage of newly established mouse tumor
models, to systematically search for liver-specific factors and mechanisms of resistance to immunotherapy. All
of the proposed experiments in this ambitious project can only be done in collaboration with Shadel, Adams and
Kaech with complementary expertise and the Cores.

## Key facts

- **NIH application ID:** 10698110
- **Project number:** 5P01AG073084-03
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Gen-Sheng Feng
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $408,425
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10698110

## Citation

> US National Institutes of Health, RePORTER application 10698110, Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy (5P01AG073084-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10698110. Licensed CC0.

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