# Elucidate and Modulate Cell Signaling in NK Cells for Glioma Treatment

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2021 · $420,175

## Abstract

Project Summary
Natural killer (NK) cells are a critical component of innate immunity and are cytolytic to tumor cells and viral-
infected cells. Oncolytic herpes simplex virus 1 (oHSV), which has recently been approved by the FDA for the
treatment of cancer, holds great potential in the treatment of glioblastoma (GBM), a highly lethal brain tumor.
However, based on our previous studies, host NK cells provide a rapid and robust response following central
nervous system (CNS) infection with oHSV, thus presenting a barrier for effective oncolytic virotherapy for
GBM. Cytotoxic genes, including granzyme B (Gzmb), determine NK cell cytolytic activity in these settings;
however, the molecular mechanisms responsible for regulating Gzmb expression are largely unknown. In this
application, our preliminary data show that Smad4, a co-Smad protein in the TGF-beta superfamily signaling
pathway, positively regulates Gzmb expression in a TGF-beta-independent manner, which correlates with
decreased anti-tumor activity in mice with an NK-specific Smad4 deficiency. Using this mouse model, we also
discovered that Smad4 positively regulates NK cell homeostasis and maturation by upregulating Blimp1, a
positive regulator of NK cell maturation. Smad4 is also a co-Smad in bone morphogenetic protein (BMP)
signaling. Our preliminary data support the hypothesis that the TGF-β-independent role of Smad4 in regulating
NK cell function is downstream of BMP signaling, which has been reported to positively regulate NK cell
function. Here, we propose to explore the mechanisms for this conceptually novel discovery and to modulate
BMP-Smad4 signaling in NK cells in the setting of oncolytic virotherapy for GBM. Our overall hypothesis is
that Smad4 positively regulates NK cell development and cytotoxicity against target cells including
oHSV-infected GBM cells, and this can be modulated by temporarily inhibiting BMP-Smad4 signaling to
enhance the efficacy of oHSV therapy. We propose an in-depth investigation into the molecular mechanisms
whereby smad4 positively regulates Gzmb expression, cytotoxicity, and development of NK cells in mice using
our aforementioned animal model and in humans using samples of patients with familial juvenile polyposis
(FJP), having a germline loss-of-function mutation in Smad4. Additionally, we also propose to modulate BMP-
Smad4 signaling to temporarily inhibit NK cell responses to oHSV to enhance its efficacy for the treatment of
GBM. These are outlined in three Aims to test our hypothesis. Aim 1 is to dissect the mechanisms by which
Smad4 positively regulates NK cell cytotoxicity against target cells. Aim 2 is to characterize the mechanisms
by which Smad4 positively regulates NK cell development. Aim 3 is to temporarily inhibit BMP-Smad4
signaling in NK cells to improve oncolytic viral therapy for GBM in vitro and in vivo. We believe that the results
of these studies will lend new insights into basic mechanisms of cytotoxic cell therapy and that explor...

## Key facts

- **NIH application ID:** 10177848
- **Project number:** 5R01AI129582-09
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Jianhua Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,175
- **Award type:** 5
- **Project period:** 2017-07-18 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177848

## Citation

> US National Institutes of Health, RePORTER application 10177848, Elucidate and Modulate Cell Signaling in NK Cells for Glioma Treatment (5R01AI129582-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10177848. Licensed CC0.

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