# Project 3: Chronic interferon and bile acid signaling as drivers of immunosuppression in age-related liver cancer

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2024 · $413,965

## Abstract

PROJECT SUMMARY – PROJECT 3
Liver cancer is a leading cause of cancer related deaths world-wide (1,2). Age is a crucial risk for acquiring
cancer as people older than 60 are more likely to develop primary liver cancer (3). A key aspect of the aging
process is the development of chronic inflammation that inhibits the homeostatic liver functions, thereby
contributing to tumor growth (4,5). Specifically, we advocate that during aging, chronic interferon (IFN) signaling
leads to upregulation of immune checkpoints in both hepatocytes and immune cells that suppress anti-tumor
immune responses. Besides upregulating immune checkpoints, chronic IFN signaling also induces various
metabolic disruptions that could act together to inhibit anti-tumor immune responses. Bile acids (BAs) are
important metabolites to consider in this regard, because the accumulation of BAs within the liver is an important
risk factor that could contribute to liver tumor initiation and progression (6,7). While liver cancers are often
infiltrated by T cells, surprisingly, this type of tumor is fairly unresponsive to immune-checkpoint blockade and
adoptive T cell therapy (8,9). Our preliminary analysis shows that BAs accumulate with age, and we hypothesize
that such excessive amount of BAs could cause suppression of infiltrating T cells and T cell directed
immunotherapies to combat liver cancer. A direct inhibitory role for BA signaling on T-cell function, especially in
the context of anti-tumor immunity, has not been well-investigated to date. Thus, we plan to study novel ways by
which persistent BA signaling influences T cell suppression within tumors, notably dissecting such suppressive
mechanisms in the context of aging as it relates to tumor progression. Metabolites such as BAs that build-up in
the liver during aging can act together with other inhibitory molecules, for example IFN-directed immune
checkpoints like PD-L1, to promote T cell dysfunction. This project at the interface of aging and cancer has great
potential to provide new and efficient ways to rejuvenate CD8+ T cell mediated immunity, thereby providing novel
avenues to prevent and treat aggressive cancers including colon, esophageal and pancreatic cancers for which
BAs can accumulate and contribute to disease pathogenesis (10). Moreover, this Project will leverage the
expertise of Dr. Feng (Project 4) for BA-signaling and liver cancer mouse models, Dr. Shadel (Project 1) for
metabolic and mitochondrial function and mechanisms of IFN-signaling and aging, and Dr. Adams (Project 2)
for mouse models of aging and age-related changes in gene expression, Dr. Sacco (Core B) for all major mouse
models and common interventions, and Dr. Shokhirev (Core C) for bioinformatic and systems-level analyses of
age related changes in the liver and tumor progression.

## Key facts

- **NIH application ID:** 10908397
- **Project number:** 5P01AG073084-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Susan M Kaech
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $413,965
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908397

## Citation

> US National Institutes of Health, RePORTER application 10908397, Project 3: Chronic interferon and bile acid signaling as drivers of immunosuppression in age-related liver cancer (5P01AG073084-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10908397. Licensed CC0.

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