# Dissecting the immunomodulatory effects of NK cells on immune responses to cancer

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $530,015

## Abstract

PROJECT SUMMARY
Current immunotherapies, such as anti-PD-1 immunotherapy, have low objective responses in patients,
necessitating the development of novel therapies that boost immune responses to cancer and responses to these
treatments. Further, most immunotherapies in the clinic, anti-PD-1 immunotherapy included, predominantly act on
T cells. While combinations of T cell-directed therapies can lead to excellent outcomes for some, most patients still
have no objective responses to combinations of these immunotherapies. Thus, it is imperative to identify novel
therapeutic targets that work synergistically with anti-PD-1 immunotherapy and other T cell-directed therapies.
Natural killer (NK) cells are innate lymphocytes that can control tumors through direct cytotoxicity or their
immunomodulatory production of cytokines and chemokines. NK cell abundance in the tumor correlates with
increased patient survival and patient responses to immunotherapies. We previously found that a key
immunomodulatory function of NK cells is their production of the cytokine FLT3LG which regulates type 1
conventional dendritic cell (cDC1) abundance in the tumor microenvironment (TME). cDC1s are an important
antigen presenting cell that shapes anti-tumor T cell responses. We found that NK cell production of FLT3LG
regulates cDC1 abundance in the TME which leads to increased patient survival and responses to anti-PD-1
immunotherapy. We hypothesize that targeting the immunomodulatory effects of NK cells in the tumor
microenvironment will lead to more protective cDC1s, better tumor-directed T cell responses, and increased
efficacy of immunotherapies. Thus, it is critically important that we define how NK cells are regulated in the tumor
microenvironment. In particular, the cellular and molecular mechanisms regulating NK cell phenotype and function
in the tumor are unknown, and the molecular mechanisms controlling NK cell production of the cytokine FLT3LG
are unknown. In Aim 1 of this project, we will determine tumor-intrinsic features that regulate NK cell phenotype
and function in the tumor. In Aim 2, we will define the mechanisms that regulate NK cell production of Flt3L. In Aim
3, we will elucidate the mechanisms regulating NK cell phenotype and function in human metastatic melanoma. To
address these aims we have developed ectopic tumor models and in vitro NK cell stimulation assays that allow us
to define the molecular mechanisms regulating NK cell production of Flt3L. We have also developed complimentary
human immunology studies of metastatic melanoma samples that allow for the study of NK cells and their
immunomodulatory effects in a translational setting. The studies outlined in this proposal will provide answers to
longstanding questions about how NK cell phenotypes and functions are regulated in the TME and will be
foundational to the development of novel immunotherapies that target the immunomodulatory effects of NK cells
to increase a patient’s immune response to ...

## Key facts

- **NIH application ID:** 10878615
- **Project number:** 1R01CA283080-01A1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Kevin C Barry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,015
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878615

## Citation

> US National Institutes of Health, RePORTER application 10878615, Dissecting the immunomodulatory effects of NK cells on immune responses to cancer (1R01CA283080-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878615. Licensed CC0.

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