# Immunosuppressive mechanisms responsible for development of non-viral liver cancer and control of its response to immune checkpoint inhibitors

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $725,319

## Abstract

PROJECT SUMMARY
This project will explore adaptive immune mechanisms that control development of hepatocellular carcinoma
(HCC), a leading cause of cancer-related deaths, and dictate its responsiveness to PD-1:PD-L1 checkpoint
inhibitors. Our team, including Michael Karin, Ph.D. and Shabnam Shalapour, Ph.D. at UCSD School of Medicine
and Hidekazu Tsukamoto, D.V.M., Ph.D. and Anthony El-Khoueiry, M.D. at USC Keck School of Medicine,
represents an ideal blend of basic researchers, translational scientists and oncologists who are interested in
HCC molecular pathogenesis and treatment, especially in HCC caused by non-alcoholic (NASH) and alcoholic
(ASH) steatohepatitis. Although the US incidence of HCC and its associated mortality have nearly tripled in the
past generation, insufficient effort has been made toward identification and development of innovative and
effective HCC therapies. However, the ideal and timely confluence of basic preclinical research and applied
clinical studies carried out by our team members has the potential to critically transform HCC treatment forever.
Together we found that chronic liver inflammation results in suppression of HCC-protective immunosurveillance
to support rapid malignant progression. This unique immunopathogenic mechanism renders HCC responsive to
drugs that disrupt the PD-1:PD-L1 checkpoint, but even the impressive response seen thus far and the selection
of patients who will benefit from this therapeutic approach can be further improved. Such improvements can only
be achieved by a deeper understanding of the mechanisms through which PD-1:PD-L1 inhibitors act, the factors
that determine their efficacy, and the causes of treatment failure. We will achieve these goals through integrated
studies of clinical specimens collected by Dr. El-Khoueiry and sophisticated, faithful and robust mouse models
of non-viral HCC developed by Drs. Tsukamoto, Shalapour, and Karin. The immune mechanisms that control
NASH- and ASH-driven HCC development in these models are highly similar to those that operate in human
patients. Using this integrated approach, we will pursue five specific aims: 1) determine whether serum IgA
concentrations correlate with therapeutic response to PD-1 blockade in patients with non-viral HCC; 2) develop
reliable mouse models of ASH-driven HCC; 3) compare the immunosuppressive mechanisms that contribute to
development of NASH- and ASH-driven HCC and control their response to PD-L1 blockade; 4) determine
whether excessive peritumoral fibrosis correlates with diminished response to PD-1 blockade in HCC patients;
and 5) determine whether agents that inhibit or attenuate stellate cell activation potentiate the response to PD-
1/PD-L1 blockade in non-viral HCC. The successful completion of these studies will result in substantial
improvements to HCC immunotherapy and will establish reliable procedures for identification of patients who are
most likely to benefit from PD-1/PD-L1 targeting drugs, advances t...

## Key facts

- **NIH application ID:** 10473837
- **Project number:** 5U01AA027681-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Anthony Boutros El-Khoueiry
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $725,319
- **Award type:** 5
- **Project period:** 2018-09-25 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473837

## Citation

> US National Institutes of Health, RePORTER application 10473837, Immunosuppressive mechanisms responsible for development of non-viral liver cancer and control of its response to immune checkpoint inhibitors (5U01AA027681-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10473837. Licensed CC0.

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