# Mechanism of CD8 regulation of natural killer cell biology

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2022 · $32,686

## Abstract

Project Summary
 Hematologic malignancies such as acute myeloid leukemia (AML) remain clinically challenging and
refractory to traditional chemotherapy approaches. For many patients, hematopoietic cell transplant (HCT) is the
only curative treatment, whereby part of the efficacy is driven by donor natural killer (NK) cells that target the
recipient’s leukemic cells. Natural killer cell adoptive therapy for AML patients represent a promising approach
for improving patient outcomes. Work done in the Fehniger lab has defined a strategy to induce a memory-like
(ML) phenotype of isolated NK cells using a stimulation with IL-12, IL-15, and IL-18 that demonstrates enhanced
proliferation, cytotoxicity, and persistence both in vitro and in vivo. A phase 1 study using ML NK cells in
relapsed/refractory AML patients showed approximately 50% of patients achieving a complete remission,
although the mechanisms driving treatment failure are not clearly understood.
 Multidimensional immune correlative analysis of donor NK cells identified a negative association between
CD8 expression on NK cells and treatment response. However, the role of CD8 on human conventional and ML
NK cells remains unknown.
 The proposed project aims to understand the mechanism by which CD8 expression impacts conventional
and ML NK cell biology, and has broad implications for understanding NK cell responses in cancer, infection,
and autoimmunity. Preliminary data demonstrate that CD8+ NK cells have a diminished proliferative capacity
compared to CD8- NK cells both in vitro and in vivo. We hypothesize that CD8 expression on donor NK cells
negatively impacts overall NK cell responses against AML. Aim 1 of this proposal focuses on determining the
mechanisms by which CD8+ conventional and ML NK cells have compromised proliferation, and the subsequent
impact on tumor control in vivo. Specifically, the contributions of telomere length, chromatin accessibility, and
metabolic differences will be investigated. Aim 2 focuses on defining the function of the CD8 molecule itself
through highly efficient CRISPR-Cas9 based knockdown, and the subsequent impact on conventional and ML
NK cell cytotoxicity, signaling, and survival. Together, these results will further inform future NK cell therapy
designs and enhance our understanding of CD8 and its contributions to fundamental aspects of NK cell biology.

## Key facts

- **NIH application ID:** 10356062
- **Project number:** 5F30AI161318-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Celia Claire Cubitt
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $32,686
- **Award type:** 5
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356062

## Citation

> US National Institutes of Health, RePORTER application 10356062, Mechanism of CD8 regulation of natural killer cell biology (5F30AI161318-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10356062. Licensed CC0.

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