# Defining the mechanisms of B7-H3 overexpression and role in neuroblastoma metastasis and immune evasion

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $36,651

## Abstract

Project Summary
Neuroblastoma is a cancer derived from the developing sympathetic nervous system and is the most commonly
diagnosed extracranial solid tumor of childhood. Despite an intensive treatment regimen of chemotherapy,
surgery, radiation, and immunotherapy, the five-year survival rate of high-risk neuroblastoma patients remains
at only 50%. The low tumor mutational burden of neuroblastoma has challenged the development of targeted-
and immuno-therapies, however moderate success has been achieved by targeting GD2 with monoclonal
antibody therapy, credentialing immunotherapeutic treatment strategies for neuroblastoma as a promising
approach. The success of GD2-targeted therapy to date has been hindered due to debilitating side effects from
on-target/off-tumor toxicity since GD2 is also expressed on pain fibers, and antigen loss as a mechanism of
therapy resistance. Therefore, there is an unmet need for the discovery of new therapeutic targets in
neuroblastoma. B7-H3, encoded by the CD276 gene, is a type 1 transmembrane protein in the B7 family of
immunoregulatory proteins and is highly expressed in many adult and pediatric cancers, including
neuroblastoma. In addition to being implicated in immunoinhibition, B7-H3 may also mediate tumor migration
and metastasis. Preclinical success of several immunotherapeutic strategies directed toward B7-H3, including
CAR-T cells and antibody drug conjugates, suggest that B7-H3 is a targetable tumor-associated antigen with
several pediatric clinical trials ongoing or planned. Therefore, it is critical to understand the oncogenic functions
of B7-H3 and how its expression is regulated to anticipate mechanisms of therapy resistance. Our central
hypothesis is that B7-H3 promotes neuroblastoma metastasis and immune evasion, and its expression is
regulated by tumor microenvironment-derived cytokines and neuroblastoma-specific transcription factors. Our
preliminary data shows that B7-H3 knockdown using CRISPRi in neuroblastoma cell lines inhibits cellular
proliferation. Additionally, ChIP-sequencing data identifies regions of MYC and MYCN binding at the B7-H3
promoter indicating a potential role of the MYC transcription factors in regulating B7-H3 expression. B7-H3
expression may also be regulated by inflammatory cytokines, as neuroblastoma cell lines upregulate B7-H3
expression following TNF-α or TGF-β exposure. Finally, recombinant human B7-H3 inhibits T cell activation,
TNF-α, and IFN-y. Uncovering how B7-H3 promotes immune evasion in neuroblastoma is crucial given the T
and NK cell-based immunotherapies undergoing clinical testing. We propose that B7-H3 is a multifunctional
protein that serves as a promising therapeutic target in neuroblastoma. This NRSA F31 will define the
mechanisms of neuroblastoma dependance on B7-H3 for metastasis and immune evasion, while also defining
mechanisms of overexpression, to inform future B7-H3-targeting therapies and ultimately improve outcomes for
patients with high-risk ne...

## Key facts

- **NIH application ID:** 10930001
- **Project number:** 5F31CA284708-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Catherine Leona-Grace Wingrove
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,651
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930001

## Citation

> US National Institutes of Health, RePORTER application 10930001, Defining the mechanisms of B7-H3 overexpression and role in neuroblastoma metastasis and immune evasion (5F31CA284708-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10930001. Licensed CC0.

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