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 (IFN?) 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.

Public Health Relevance

We now have clear evidence that NK cells progressively undergo a process of ?exhaustion?, described as a state of cellular dysfunction, from early to late stage melanoma. Characterizing NK cell dysfunction in melanoma will be critical towards developing approaches that restore immunity, in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA201189-05
Application #
9961502
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Kuo, Lillian S
Project Start
2016-07-27
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Saxena, Mansi; Balan, Sreekumar; Roudko, Vladimir et al. (2018) Towards superior dendritic-cell vaccines for cancer therapy. Nat Biomed Eng 2:341-346
Saxena, Mansi; Bhardwaj, Nina (2018) Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment. Trends Cancer 4:119-137
Audenet, François; Farkas, Adam M; Anastos, Harry et al. (2018) Immune phenotype of peripheral blood mononuclear cells in patients with high-risk non-muscle invasive bladder cancer. World J Urol 36:1741-1748
Saxena, Mansi; Bhardwaj, Nina (2017) Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr Opin Immunol 47:35-43
Gonzalez-Gugel, Elena; Saxena, Mansi; Bhardwaj, Nina (2016) Modulation of innate immunity in the tumor microenvironment. Cancer Immunol Immunother 65:1261-8