# NK cell exhaustion in metastatic melanoma

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $387,731

## Abstract

Project summary
 NK cells are key participants in the initial immune response to tumorigenesis and virus infections,
equipped to respond rapidly through induction of cytokines and deployment of cytotoxic activity. A dynamic
balance of positive and negative signals regulates NK cell target cell recognition and lysis, through
engagement of a variety of activation and inhibitory receptors. However, as cancers advance there is
accumulating evidence that NK cells become progressively dysfunctional. NK cell “exhaustion,” could explain
the failure of NK cells to contain tumor growth in advanced cancers. While NK cell hyporesponsiveness has
been described in various malignancies, there is little characterization of an “exhausted NK cell state” in
metastatic disease, nor of the mechanisms that might underlie this phenotype. We now have evidence that NK
cells progressively undergo exhaustion in late stage melanoma. Melanoma associated NK cells are
characterized by a failure to proliferate, to produce interferon gamma (IFNγ) or to kill target cells. They (i) down
regulate activation receptors, IL-2R subunits and NK cell regulatory transcription factors (T-bet, Eomes), (ii)
upregulate inhibitory receptors and (iii) express high levels of the checkpoint molecule Tim-3, a phenotype that
is consistent with “NK cell exhaustion”. Significantly, blockade of Tim-3 substantially reverses this phenotype
and state of exhaustion in vitro (Can. Imm Res. 2014). Most strikingly however, we find that patients who have
a clinical response to ipilimumab treatment spontaneously restore their NK cell function, despite the fact that
these cells express little or no CTLA-4 (or PD-1 or PD-L1), possibly through reversal of tumor-associated
systemic immune suppression. Characterizing NK cell dysfunction in melanoma, therefore, will be critical to
understanding the modulation of NK cell biology in the tumor microenvironment (TME), and ultimately towards
developing approaches that restore both innate and adaptive immunity, in vivo.
 Although the survival of advanced melanoma patients (stage IV) has been extended by interventions
that reverse T cell exhaustion, we hypothesize that reversal of exhaustion in NK cells will contribute towards
the full restoration of immune responses that are required to eliminate melanoma cells. To address this
hypothesis, we aim to define the spectrum of NK cell exhaustion in melanoma and identify molecular/protein
targets that potentiate NK cell exhaustion (Aim 1). Secondly, we will determine if NK cell exhaustion can be
reversed in response to checkpoint blockade inhibition, and identify associated biomarkers (Aim 2). In Aim 3,
we will develop murine models to define and test interventions that reverse NK cell exhaustion. Characterizing
NK cell dysfunction in melanoma will be critical towards developing approaches that restore immunity, in vivo.

## Key facts

- **NIH application ID:** 9961502
- **Project number:** 5R01CA201189-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Nina Bhardwaj
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,731
- **Award type:** 5
- **Project period:** 2016-07-27 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961502

## Citation

> US National Institutes of Health, RePORTER application 9961502, NK cell exhaustion in metastatic melanoma (5R01CA201189-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9961502. Licensed CC0.

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