CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription...

Area of Science:

• Immunology
• Cancer Biology
• Molecular Cell Biology

Background:

• Natural killer (NK) cells are crucial for anti-tumor immunity, utilizing activating receptors like CD226.
• Negative regulatory transcription factors, such as FOXO1, often suppress NK cell effector functions.
• The precise interplay between activating receptors and negative regulators in NK cell-mediated tumor cell recognition remains incompletely understood.

Purpose of the Study:

• To elucidate the regulatory mechanism by which CD226 influences NK cell cytotoxicity against tumor cells.
• To investigate the role of the transcription factor FOXO1 in CD226-mediated NK cell effector functions.
• To define the signaling pathway linking CD226 engagement to the modulation of NK cell anti-tumor activity.

Main Methods:

• Gene-expression analysis of NK cells from wild-type and CD226-deficient mice bearing syngeneic tumors.
• In vitro cytotoxicity and stimulation assays to assess NK cell killing of tumor target cells.
• Biochemical assays to evaluate FOXO1 phosphorylation status upon CD226 engagement and in response to pharmacological inhibitors.

Main Results:

• CD226 deficiency in NK cells led to dysregulated expression of FOXO1-controlled genes and impaired tumor cell killing.
• Engagement of CD226 by its ligand CD155 induced phosphorylation and inactivation of FOXO1, enhancing NK cell cytotoxicity.
• Inhibition of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector functions, confirming FOXO1 inactivation as a key downstream event.

Conclusions:

• CD226 plays a critical role in NK cell-mediated tumor surveillance by facilitating the inactivation of the inhibitory transcription factor FOXO1.
• The CD226-CD155 interaction triggers a signaling cascade leading to FOXO1 phosphorylation, thereby promoting NK cell cytotoxicity.
• This study defines a novel molecular pathway by which CD226 regulates NK cell responses, offering potential therapeutic targets for cancer immunotherapy.