# DKK2 regulates NK activation and tumor immunity

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $513,312

## Abstract

Project Summary:
Cancer is a leading cause of death, but recent emergence of immunotherapies including the immune
checkpoint inhibitors has offer promising new cancer treatment options. It is also evident that tumor immunity is
highly complex and incompletely understood. The better understanding of tumor immune regulation may lead
to identification of additional targets for cancer immunomodulatory therapy. In our preliminary studies, we
found Dickkopf-2 (DKK2), a protein previously known for its antagonism of the Wnt-β-catenin signaling, as
being an inhibitor of natural killer cell activation. Genetic inactivation or antibody-mediated neutralization of
DKK2 impedes tumor progression in a mouse genetic intestinal tumor model and syngeneic tumor graft models.
The action of DKK2 neutralization on grafted tumor progression depends on immune system, specifically on
natural killer (NK) cells, as DKK2 neutralizing antibody loses its effectiveness in the NSG immunodeficient mice
and in mice NK1.1+ cells are depleted. DKK2 neutralization increases activation of tumor infiltrated NK cells,
accompanied by increases in tumor cell apoptosis. These effects of the antibody can be recapitulated in a co-
culture of primary mouse NK cells and tumor cells. Moreover, DKK2 protein can directly inhibit activation of NK
cells by IL-15 probably by impairing STAT5 nuclear localization. These preliminary results together suggest a
hypothesis that DKK2 may promote tumor formation by inhibiting IL-15 signaling and NK cell activation. In this
study we will extend our preliminary studies to further test the hypothesis. The specific aims are: 1) To
investigate how DKK2 suppresses NK cell activation. 2) To further characterize the mechanism of action for
DKK2 inhibition to impede tumor progression. 3) To further evaluate the therapeutic potentials of DKK2
neutralization in cancer treatment using mouse models.

## Key facts

- **NIH application ID:** 10064071
- **Project number:** 5R01CA214703-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Dianqing Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $513,312
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064071

## Citation

> US National Institutes of Health, RePORTER application 10064071, DKK2 regulates NK activation and tumor immunity (5R01CA214703-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064071. Licensed CC0.

---

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