NK cells in the tumor microenvironment and thioredoxin activity
Theresa L. Whiteside
Theresa L. Whiteside
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NK cells in the tumor microenvironment and thioredoxin activity

Abstract

NK cells are responsible for defense against viral infections and cancer. Although activated NK cells are armed to combat tumors, the tumor microenvironment (TME) contains ROS, which suppress NK cell antitumor activity. In this issue of the JCI, Yang, Neo, and colleagues explored NK cell resistance to oxidative stress in vitro and in human non–small-cell lung cancer (NSCLC). High surface thiol density and elevated expression of the ROS scavenger thioredoxin (Trx1) protected NK cells from ROS. Trx1 and thiol levels were higher in IL-15– than in IL-2–primed NK cells. Tumor-infiltrating Trx1+ NK cells were present in patients with NSCLC with elevated ROS levels in the tumor. Smokers scored higher for the ROS signature, which predicted poor prognosis, compared with nonsmokers. This study explains how activated NK cells survive in the ROS-rich TME and suggests that smokers with lung cancer may benefit from therapies using IL-15–primed NK cells.

Authors

Theresa L. Whiteside

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Figure 1

The emergence of NK cells from obscurity to biological prominence.

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The emergence of NK cells from obscurity to biological prominence. (A) W...
(A) When discovered in the 1980s, NK cells were recognized as CD45+CD56+CD16+ effector lymphocytes that did not express the T cell receptor or the B cell receptor. (B) Today, the NK cell surface is decorated by multiple receptors, only some of which are shown above. Sixteen activating proteins (NCRs, green), at least ten different KIRs, and various inhibitory receptors such as NKG2D or TRAIL (red), chemokine receptors (e.g., CXCR3 or CXCR4) and cytokine receptors (including IL-2R and IL-15R, blue), and adhesion molecules (e.g., DNAM-1, yellow) are expressed on NK cells. Further, NK cells produce a variety of cytokines and soluble factors that modulate functions of cells interacting with NK cells. NK cell–associated receptors and ligands are reported with regular frequency, as functionally diverse subsets of trNK cells are discovered and characterized. The study by Yang, Neo, and colleagues (11) reports that Trx1 content increases in activated NK cells and that the levels of thiols (purple) are upregulated on the cell surface, providing a protective screen against ROS.