# Elucidating the role of EOMES in Memory-Like NK cell Differentiation

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2022 · $32,686

## Abstract

Project Summary
 Natural killer (NK) cells are innate lymphoid cells that are crucial for host defense from viral infections
and tumor cells. The ability of NK cells to recognize and kill malignant cells provides a strong premise to advance
them as a cellular therapy in the clinical setting. While NK cell-based therapies are being explored in clinical
trials, issues with persistence and in vivo functionality have been identified as limitations to their clinical
application. Our lab pioneered cytokine-induced memory-like (ML) NK cells that are generated after brief
activation with IL-12, IL-15, and IL-18. This overcomes many of the shortcomings of conventional NK cells as a
cellular therapy. ML NK cells exhibited enhanced functionality, cytotoxicity, and persistence in a phase I clinical
trial for acute myeloid leukemia (AML), with many patients achieving complete remissions from this novel
intervention. Despite the translational advancement, there is little known about the underlying mechanisms of
ML reprogramming in NK cells. Clarifying the molecular programs that drive the ML phenotype will have broad
implications for optimizing NK cells as a cellular-based therapy for hematological malignancies.
 The proposed project aims to better understand the mechanisms of ML NK cell differentiation with a focus
on the role of EOMES. EOMES is a T-box transcription factor (TF) that is essential for NK cell development from
hematopoietic stem cells and has been implicated in generating memory in CD8+ T cells. Data from our lab
demonstrated that EOMES deletion prior to activation with cytokines abrogated ML NK cell differentiation,
suggesting that EOMES plays a key role in ML reprogramming. We hypothesize that activation with IL-12/15/18
triggers a molecular reprogramming of conventional NK cells to ML NK cells mediated by EOMES to induce a
unique transcriptional profile and poised epigenetic state, which facilitates the enhanced functionality of ML NK
cells upon restimulation by cytokines or a tumor cell. Aim 1 of this proposal focuses on determining the memory
differentiation phase that requires EOMES. Specifically, we will assess the requirement of EOMES during
initiation (prior to IL-12/15/18 activation) and differentiation (after IL-12/15/18 activation) using CRISPR/Cas9
deletion. Aim 2 focuses on defining the transcriptional and epigenetic landscape induced by EOMES in the
different phases of ML reprogramming through CRISPR/Cas9 knockdown, single-cell RNAseq, and single-nuclei
ATACseq, as well as defining the genes regulated by EOMES in ML NK cells using Cut&Run. Together, these
results will reveal mechanisms of ML NK cell differentiation driven by EOMES, further advancing the potential of
ML NK cell therapies and enhancing our understanding of ML NK cell biology.

## Key facts

- **NIH application ID:** 10462945
- **Project number:** 1F31GM146361-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jennifer Tran
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,686
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462945

## Citation

> US National Institutes of Health, RePORTER application 10462945, Elucidating the role of EOMES in Memory-Like NK cell Differentiation (1F31GM146361-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10462945. Licensed CC0.

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