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Functional and metabolic targeting of natural killer cells to solid tumors

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Abstract

Background

The unique ability of NK cells to target cancer cells without antigen specificity makes them an attractive prospect for immunotherapy of solid tumors. However, the complexity of the tumor microenvironment (TME), particularly its heterogeneity and associated immunosuppressive properties, enables solid tumor cells to escape NK cell immune-surveillance by impairing their infiltration and cytotoxic functions. As a result, NK cells that have been able to infiltrate solid tumors are dysfunctional, exhausted and metabolically and functionally impaired. Understanding the status of NK cells in solid tumors and the interplay between the tumor-promoting functions of the TME and the immunometabolic reprogramming events that NK cells endure as a result is essential to developing approaches to improve the clinical outcome of NK cell-based immunotherapies against solid tumors.

Conclusions

In this review, we address the current knowledge on the presence and immunometabolic roles of NK cells in solid tumors as well as the strategies developed to restore NK cell activities in these conditions, with the ultimate goal of enhancing persistence, trafficking, cytotoxicity and metabolic functions.

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Abbreviations

ADO:

adenosine

HLA:

human leukocyte antigen

IFN-γ:

interferon-γ

TME:

tumor microenvironment

ILC:

innate lymphoid cell

NK:

natural killer

ITIM:

immunoreceptor tyrosine-based inhibitory motif

PGE2:

prostaglandin E2

LDHA:

lactate dehydrogenase A

IL:

interleukin

A2AR:

adenosine A2 receptor

MDSC:

myeloid-derived suppressor cell

Treg :

regulatory T cell

ADCC:

antibody-dependent cellular cytotoxicity

NKG2D:

natural killer group 2 D

NKG2A:

natural killer group 2 A, KIR, killer immunoglobulin receptor

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

TRAIL:

TNF-related apoptosis-inducing ligand

TNF-α:

tumor necrosis factor α

PD-1/L1:

programmed death protein-1/ligand

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Funding

This work was supported, in part, by a Ralph W. and Grace M. Showalter Research Trust award and a Walther Cancer Foundation Embedding Grant.

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  1. Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA

    Jiao Wang & Sandro Matosevic

  2. Center for Cancer Research, Purdue University, West Lafayette, IN, 47906, USA

    Sandro Matosevic

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  1. Jiao Wang
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J.W. did primary research and wrote the initial draft of the manuscript. S.M. oversaw preparation of the manuscript and edited the final draft.

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Wang, J., Matosevic, S. Functional and metabolic targeting of natural killer cells to solid tumors. Cell Oncol. 43, 577–600 (2020). https://doi.org/10.1007/s13402-020-00523-7

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