# The role of Notch signaling in human natural killer cell functional maturation

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2020 · $39,721

## Abstract

PROJECT SUMMARY/ABSTRACT
Our long-term goal in this project is to elucidate the mechanisms of human natural killer cell development in
order to apply the processes of NK cell biology in the treatment of cancer. Natural killer (NK) cells recognize
malignant cells lacking self-MHC molecules on their surface, thus targeting them for perforin-mediated
cytotoxicity. NK cells comprise an important role in the innate immune response to malignancy, and indeed
cancers such as acute myeloid leukemia (AML) have been shown to have impaired NK cell development and
function. Therefore, understanding the yet unknown mechanisms regulating NK cell maturation in both the
normal and disease settings will improve translational research efforts for cancer therapy. Our ongoing work
investigates NK cell developmental pathways occurring in secondary lymphoid tissues (SLTs; including tonsils
and lymph nodes). In our current studies, we observed that activation of the Notch signaling pathway results in
a key transition during development from a non-functional phenotype to a functionally mature NK cell. Moreover,
we detected constitutive expression of the transcriptionally-active domain of Notch in mature NK cells freshly
isolated from tonsils, thus supporting the physiologic importance of Notch in regulating the functional phenotype
of mature NK cells. We hypothesize that Notch signaling in the SLT microenvironment regulates the
developmental transition from immature to functional NK cells. We further hypothesize that signaling through the
aryl hydrocarbon receptor (AHR), which we observe is activated in AML, alters Notch signaling to inhibit NK cell
development. Thus our aims are 1) to determine the mechanism by which Notch is activated in SLTs to promote
NK cell functional maturation; and 2) to determine how AHR modulates Notch to antagonize NK cell maturation.
To test this hypothesis, we will perform in vitro culture studies and in vivo adoptive transfer experiments using
NK and other SLT-resident cells isolated from human tonsils. We will identify the direct gene targets of activated
Notch in NK cells to determine how Notch regulates the transcription of critical molecules for NK cell function.
Finally, we will identify how AHR modulates Notch signaling in NK cells. The overall significance of this project
will address a relevant gap in knowledge regarding the regulation of human NK cell maturation in the SLT
microenvironment. This project represents a novel and innovative approach to cancer immunology because it
combines both mechanistic studies of an important signaling pathway, and also seeks to identify how cancers
such as AML can evade the human immune system. Successful completion of these aims will improve our
understanding of the normal processes of NK cell development with the goal of applying these discoveries toward
novel immune-based therapies for cancer.

## Key facts

- **NIH application ID:** 9921194
- **Project number:** 5F30CA236063-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Ansel Peter Nalin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,721
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921194

## Citation

> US National Institutes of Health, RePORTER application 9921194, The role of Notch signaling in human natural killer cell functional maturation (5F30CA236063-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9921194. Licensed CC0.

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