# Targeting posttranslational modifications of B7-H4 in carcinogenesis and therapy

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $1

## Abstract

Targeting post-translational modifications of B7-H4 in carcinogenesis and therapy
The goal of this project is to determine the impact of interplay between glycosylation and ubiquitination of B7-H4
in breast carcinogenesis and anti-breast cancer therapy. B7-H4, also known as V-set domain containing T cell
activation inhibitor 1 (VTCN1), acts as an immune checkpoint protein whose local abnormal accumulation is
correlated with poor prognosis of various types of cancers including triple negative breast cancer (TNBC). While
a current TCGA study suggests the critical role of B7-H4 in conferring tumor sensitivity to chemotherapy drugs
and immune checkpoint inhibitors, how B7-H4 is regulated and how its deregulation contributes to breast
carcinogenesis and tumor drug response remain unknown. Results from our recent purification of the B7-H4
protein complex revealed that 2 critical enzymes, AMFR and STT3 complex, tightly interact with and regulate
B7-H7. While the E3 ubiquitin ligase AMFR catalyzes ubiquitination of B7-H4 followed by degradation, we
observed that glycosylation of B7-H4 protein by the STT3 complex (a glycosyltransferase) results in the
stabilization of B7-H4 and inhibition of doxorubicin-induced immunogenic cell death (ICD). Elevation of B7-H4
levels due to enhanced B7-H4 glycosylation counteracts B7-H4 ubiquitination, which in turn suppresses
endoplasmic reticulum stress-mediated phagocytosis in response to chemotherapy drugs, a critical step in
triggering mass tumor eradication by ICD. We further demonstrated that blockade of B7-H4 glycosylation by
NGI-1, a novel protein glycosylation inhibitor, significantly enhances B7-H4 ubiquitination and subsequent
degradation, resulting in promotion of tumor killing efficacy due to increased phagocytosis by dendritic cells and
their capacity to elicit CD8+ interferon-γ-producing T cell responses. In this project, we plan to test the
hypothesis that deregulation of B7-H4 by the crosstalk between glycosylation and ubiquitination promotes
TNBC tumor evasion from chemotherapy and blockade of B7-H4 glycosylation by NGI-1 could be a new strategy
for anti-TNBC treatment. We propose the following specific aims to pursue this goal: (1) to determine the
mechanism by which interplay between glycosylation and ubiquitination regulates B7-H4-orchestrated
phagocytosis; (2) to determine the physiological relevance of STT3-mediated glycosylation and AMFR-facilitated
ubiquitination in B7-H4-mediated ICD in response to chemotherapy drugs; and (3) to determine the clinical
relevance of blockade of B7-H4 glycosylation by NGI-1 in anti-TNBC treatment using various preclinical murine
models.

## Key facts

- **NIH application ID:** 10361572
- **Project number:** 5R01CA258765-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Yong Wan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2021-11-09 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10361572

## Citation

> US National Institutes of Health, RePORTER application 10361572, Targeting posttranslational modifications of B7-H4 in carcinogenesis and therapy (5R01CA258765-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10361572. Licensed CC0.

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