Interleukin-35 impairs human NK cell effector functions and induces their ILC1-like conversion with tissue residency...

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• Natural Killer (NK) cells are crucial for immune responses but their function declines in chronic inflammation via unknown mechanisms.
• Interleukin-35 (IL-35) is a cytokine with known immunomodulatory effects.

Purpose of the Study:

• To investigate the impact of IL-35 on human NK cell function and plasticity.
• To explore the role of IL-35 in the tumor microenvironment and its association with prognosis.

Main Methods:

• In vitro studies on human NK cells exposed to IL-35.
• Analysis of public cancer patient datasets to assess IL-35 expression and NK/ILC1-like cell presence in tumors.

Main Results:

• IL-35 inhibits NK cell proliferation, pro-inflammatory, and cytotoxic functions.
• IL-35 induces NK cell conversion to CD9+CD103+CD49a+ ILC1-like cells through TGF-β.
• IL-35-producing cells and IL-35-receptor-expressing NK/ILC1-like cells are found in tumors, correlating with poor prognosis.

Conclusions:

• IL-35 drives NK cell plasticity, leading to tissue-resident phenotypes and reduced effector functions.
• IL-35 is implicated in pathophysiological contexts and represents a potential target for immunotherapy to enhance NK cell activity.