# A Novel Target in The Tumor Myeloid Compartment for Hepatocellular Carcinoma

> **NIH NIH P01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $453,620

## Abstract

PROJECT 3: SUMMARY
Given the limited clinical benefits of the current treatments for hepatocellular carcinoma (HCC), there is an
urgent need for novel approaches to improve patient outcomes. This project seeks to understand the host
molecular determinants in immune surveillance and therapeutic responsiveness of HCC by focusing on the
innate pattern recognition receptor SRA/CD204 that is primarily expressed on cells of myeloid origin. In this
project, we will test the hypothesis that SRA acts as a previously unrecognized immune checkpoint on myeloid
cells by impairing immune recognition during hepatocarcinogenesis and facilitating therapeutic resistance
particularly to immune checkpoint inhibitors (ICIs). This hypothesis is supported by our preliminary data
showing increased immune-mediated regression of HCC and HCC susceptibility to anti-PD-1 therapy in the
absence of SRA. The overall goals of this project are to examine SRA-centric molecular pathways within the
myeloid cell compartment of the tumor microenvironment that promote immune tolerance and develop novel
combination strategies using therapeutic antibodies for SRA to achieve durable control of HCC. To accomplish
the objectives, we will first establish a critical role of SRA for promoting cancer-immune evasion using mouse
models of HCC including the oncogene MYC-driven hepatocarcinogenesis as well as experimental tools that
we have generated (e.g., an SRA conditional knockout mouse). Additionally, we will mechanistically
understand the SRA function in defining HCC responsiveness to ICI-based immunotherapy. Considering the T-
cell suppressive activity of a soluble form of SRA, we will also examine its alteration during disease
progression in mouse models and in human HCC. Lastly, we will evaluate SRA-targeting antibody blockade as
a novel means to reinvigorate immune activation that can be rationally combined with ICIs and/or targeted
therapy (e.g., MYCi975) for safe and effective HCC control. It is anticipated that successful completion of the
proposed research via synergistic collaborations with other projects of the ELEVATE P01 will help fill the
scientific gap in understanding host molecular components that can govern cancer-immune escape and
treatment resistance. Importantly, validation of blocking antibodies for SRA may lead to an innovative strategy
to reprogram the immune landscape of HCC and improve the treatment outcomes for patients.

## Key facts

- **NIH application ID:** 10849090
- **Project number:** 1P01CA275740-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Xiang-Yang Shawn Wang
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,620
- **Award type:** 1
- **Project period:** 2024-08-08 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849090

## Citation

> US National Institutes of Health, RePORTER application 10849090, A Novel Target in The Tumor Myeloid Compartment for Hepatocellular Carcinoma (1P01CA275740-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10849090. Licensed CC0.

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