NK cells in the tumor microenvironment and thioredoxin activity

Area of Science:

• Immunology
• Cancer Biology
• Cellular Stress Response

Background:

• Natural killer (NK) cells are crucial for immune surveillance against viral infections and cancer.
• The tumor microenvironment (TME) often contains high levels of reactive oxygen species (ROS), which can impair NK cell antitumor functions.
• Understanding NK cell mechanisms of resistance to oxidative stress is vital for developing effective cancer immunotherapies.

Purpose of the Study:

• To investigate the mechanisms underlying NK cell resistance to oxidative stress within the TME.
• To evaluate the role of thioredoxin (Trx1) and surface thiols in protecting NK cells from ROS.
• To explore the potential of IL-15-primed NK cells in overcoming ROS-mediated suppression in non-small-cell lung cancer (NSCLC).

Main Methods:

• In vitro assessment of NK cell responses to oxidative stress.
• Analysis of thioredoxin (Trx1) expression and surface thiol density in NK cells primed with IL-15 versus IL-2.
• Examination of tumor-infiltrating NK cells and ROS levels in human NSCLC samples, correlating with smoking status and prognosis.

Main Results:

• High surface thiol density and elevated thioredoxin (Trx1) expression were identified as key factors protecting NK cells from ROS.
• IL-15-primed NK cells exhibited higher Trx1 and thiol levels compared to IL-2-primed NK cells.
• Tumor-infiltrating NK cells expressing Trx1 were found in NSCLC patients with high intratumoral ROS; a ROS signature correlated with poor prognosis, especially in smokers.

Conclusions:

• Activated NK cells can survive in ROS-rich TME through mechanisms involving surface thiols and Trx1.
• IL-15-primed NK cells demonstrate enhanced resistance to oxidative stress, offering a potential therapeutic advantage.
• Therapies utilizing IL-15-primed NK cells may benefit smokers with lung cancer, particularly those with a high ROS signature.