NK cell function down regulated by HMGB2 through ANGPT1/PI3K/AKT pathway and its effect on esophageal squamous...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Natural killer (NK) cells are vital for anti-tumor immunity but are often suppressed within the tumor microenvironment.
• The role of High-mobility group box 2 (HMGB2) in regulating NK cell function, especially in esophageal squamous cell carcinoma (ESCC), remains largely unknown.

Purpose of the Study:

• To investigate the impact of HMGB2 on NK cell function in ESCC.
• To elucidate the underlying molecular mechanisms by which HMGB2 influences NK cell-mediated anti-tumor activity.

Main Methods:

• Transcriptomic and proteomic analyses of peripheral blood mononuclear cells (PBMCs) from ESCC patients and healthy donors.
• Flow cytometry to quantify HMGB2 expression in NK cells.
• RNA interference and CRISPR/Cas9 to modulate HMGB2 levels in NK-92 cells.
• Assessment of NK cell cytotoxicity and cytokine production (granzyme B, perforin, IFN-γ, TNF-α).

Main Results:

• HMGB2 was upregulated in NK cells from ESCC patients, correlating with advanced tumor stage.
• HMGB2 silencing or knockout significantly enhanced NK cell cytotoxicity and cytokine production against ESCC cells.
• HMGB2 depletion induced ANGPT1 expression and activated the PI3K/AKT pathway, which was crucial for the enhanced NK cell function.

Conclusions:

• HMGB2 inhibits NK cell-mediated anti-tumor immunity in ESCC.
• HMGB2 depletion enhances NK cell cytotoxicity through the ANGPT1/PI3K/AKT signaling pathway.
• Targeting HMGB2 may represent a novel therapeutic strategy to augment NK cell-based immunotherapy for ESCC.