# Exploiting NKG2C on adaptive NK cells for Immunotherapy

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2021 · $46,764

## Abstract

Project Summary/Abstract
 Acute myeloid leukemia (AML) is a challenging disease to cure. The only known “cure” currently is
hematopoietic stem cell transplantation (HSCT) which requires conditioning prior to transplantation. The
population that AML affects does not tolerate myeloablative conditioning well so a reduced intensity conditioning
is used instead. However, the relapse rate is unacceptably high in patients that receive reduced intensity
conditioning. Immunotherapy is a promising new field for treatment of all cancer types and we aim to improve
immunotherapy for AML patients. The benefits of targeting NK cells lie within its inherent tumor surveillance
ability. Adaptive NK cells, which are expanded after cytomegalovirus (CMV) reactivation, are a subtype of NK
cells that display enhanced killing and cytokine production. Adaptive NK cells are considered adaptive because
of their memory-like phenotype, showing enhanced activation following re-exposure. Adaptive NK cells are also
associated with lower relapse following HSCT. Adaptive NK cells are easily identified as CD57+NKG2C+. The
function of NKG2C has not been thoroughly defined on adaptive NK cells. NKG2C binds to HLA-E, a non-
classical major histocompatibility complex (MHC) class I molecule, with peptide specificity to activate NK cells.
NKG2C+ cells also downregulate NKG2A, a family member of NKG2C that also binds to HLA-E with peptide
specificity but inhibits NK cells. Our proposal aims to exploit NKG2C on adaptive NK cells for tumor
immunotherapy. In Aim 1, we look at the role of NKG2C specifically on adaptive NK cells. We will use a cell line,
K562, that lack MHC class I molecules resulting in potent NK cell activation due to lack of inhibition. We will
manipulate these cells to express HLA-E (K562-E) and with these cells to determine whether there is a signaling
function through NKG2C that is unique to adaptive NK cells or whether it is the decrease in NKG2A expression
and subsequent reduction of inhibition in adaptive NK cells that leads to their enhanced function. We can use
peripheral blood NK cells to study the function of NKG2C on adaptive NK cells, but the number of adaptive NK
cells in humans is variable. In Aim 2, we will use induced pluripotent stem cell (iPSC) derived NK cells (iNK) with
transduced NKG2C to kill tumor cells. We will specifically target tumor cells using a Trispecific Killer Engager
that activates NKG2C on the iNK, linking them with tumor target while simultaneously stimulating NKG2C and
IL15 receptor. Aim 2 creates a specific translational therapy that can be scaled for clinical trials. Overall, this
project aims to exploit NKG2C as a functional receptor for immunotherapy.

## Key facts

- **NIH application ID:** 10135680
- **Project number:** 5F30CA232481-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Emily Chiu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,764
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135680

## Citation

> US National Institutes of Health, RePORTER application 10135680, Exploiting NKG2C on adaptive NK cells for Immunotherapy (5F30CA232481-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135680. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*