# Elucidation of Human Natural Killer Cell Development

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $538,711

## Abstract

PROJECT SUMMARY
This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development
in the healthy state and in the setting of uterine endometrial carcinoma (EC). NK cells are cytotoxic “group 1”
innate lymphoid cells (ILCs) that play myriad roles in immunity and are vital to controlling malignant
transformation. NK cells undergo terminal differentiation and maturation in various tissues throughout the
body, leading to a broad spectrum of NK cell phenotypes and functions. So-called conventional NK cells (cNK)
that arise in secondary lymphoid tissues and predominate in the blood have established roles in
complementing T cell-mediated immune surveillance. In contrast, specialized tissue-resident NK cells (trNK)
and their close cousins, ILC1s, develop in various tissues and are retained there to carry out distinct functions.
In the uterus, trNK cells and ILC1s are physiologically designed to support and promote pregnancy by
promoting placental tissue invasion, immune suppression, and angiogenesis. We hypothesize that in the
setting of EC the normal processes of uterine trNK cell and ILC1 development and function are co-opted by
the tumor cells to promote their growth and invasion. Our goals in this proposal are to gain a comprehensive
understanding of the cellular and molecular components that regulate human NK cell development in healthy
tissues and to determine how these processes are impacted in the setting of EC. Our two specific aims are: 1)
To define NK cell and ILC1 developmental pathways in human tissues; and 2) To determine how NK cell
development and function are shaped by human EC. In particular, in Aim 1 we will test the hypothesis that all
NK cells and ILC1s stem from a common group 1 ILC precursor cell, which we have recently identified in
human lymphoid tissues. We propose a series of experiments to test our hypothesis and to determine the
molecular regulation of the NK cell versus ILC1 developmental axis stemming from the novel precursor cell.
Further, we will elucidate the developmental pathways of NK cells and ILC1s in the healthy human uterus,
testing the hypothesis that uterine NK cells and ILC1s also stem from a similar group 1 ILC precursor cell but
ultimately terminally differentiate through pathways distinct from those in lymphoid tissues. In Aim 2 we will
test the hypothesis that NK cell development from the common group 1 ILC precursor is skewed towards the
production of ILC1s and poorly cytotoxic uterine trNK cells that are permissive if not promoting of tumor
growth. Through our proposed studies we will determine how NK cell development, functional diversity, and
plasticity are shaped by EC. The clinical importance of these studies lies in the fact that EC is the most
common gynecologic malignancy in the United States and is the sixth leading cause of cancer death in
women. Further, we predict that the knowledge gained from our studies will improve our fundamental
understand of huma...

## Key facts

- **NIH application ID:** 10828360
- **Project number:** 5R01CA208353-07
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** AHARON G FREUD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $538,711
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828360

## Citation

> US National Institutes of Health, RePORTER application 10828360, Elucidation of Human Natural Killer Cell Development (5R01CA208353-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828360. Licensed CC0.

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