# Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma

> **NIH NIH R37** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $367,259

## Abstract

PROJECT SUMMARY (from parent application)
Hepatocellular carcinoma (HCC) represents a major health problem, causing more than 700,000 deaths
annually worldwide. Although HCC treatment has greatly improved over the last decades, most HCC patients
diagnosed at advanced stages are ineligible for curative ablative therapies such as liver resection or
transplantation. Until recently, the only FDA-approved therapies for such patients were sorafenib and
regorafenib, used as first-line and second-line therapy, respectively. Unfortunately, these two closely related
multikinase inhibitors provide limited survival benefits. In September 2017, nivolumab, a PD-1 (programmed
cell death 1) immune checkpoint inhibitor, was granted accelerated approval by the FDA for HCC treatment in
second line, after the promising results obtained in a phase II clinical trial (NCT01658878). Despite some HCC
patients show unprecedented responses with nivolumab, not all patients respond, indicating the existence of
mechanisms that drive resistance to anti-PD-1 therapy and highlighting the urgent need to identify biomarkers
for optimal patient selection and strategies to overcome resistance. Studies in other tumor types demonstrate
that different tumor-intrinsic oncogenic pathways, such as PI3K or WNT/β-catenin, promote immune escape
and confer resistance to anti-PD-1 therapy but also inform patient stratification and strategies to overcome
resistance. Our central hypothesis is that specific oncogenic signaling pathways activated in HCC amplify the
mechanisms of immune evasion and thereby impair the response to anti-PD-1 therapy. By using a novel
mouse model of HCC immune surveillance that we have recently created, we have recently demonstrated that
CTNNB1 (β-catenin), PTEN, and KMT2C (MLL3), three genes frequently altered in human HCC, are involved
in immune escape, demonstrating the feasibility of the project. Moreover, CTNNB1 activation confers
resistance to anti-PD-1 blockade and could potentially serve as a biomarker for patient exclusion. Here, by
combining this novel mouse model, human HCC samples, and transcriptional and immune profilings, we will
establish the signaling pathways that promote immune escape in HCC, the underlying mechanisms of immune
escape, and their effects on response to anti-PD-1 therapy.

## Key facts

- **NIH application ID:** 10889027
- **Project number:** 5R37CA230636-07
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Amaia Lujambio
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $367,259
- **Award type:** 5
- **Project period:** 2018-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889027

## Citation

> US National Institutes of Health, RePORTER application 10889027, Tumor-intrinsic signaling pathways restrict anti-tumor immunity in hepatocellular carcinoma (5R37CA230636-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10889027. Licensed CC0.

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