Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• S100A8/A9 is a proinflammatory protein implicated in inflammatory diseases and tumor promotion.
• Its role in predicting cancer prognosis remains controversial.
• Understanding its in vivo function in the tumor microenvironment is crucial.

Purpose of the Study:

• To investigate the in vivo role of S100A8/A9 in the tumor microenvironment.
• To elucidate the mechanism by which S100A8/A9 influences tumor growth and immune cell activity.

Main Methods:

• Syngeneic mouse model using Pan02 cells engineered to express S100A8 and S100A9.
• Flow cytometry to analyze immune cell populations (NK cells) and cytokine production (IFN-γ).
• In vitro co-culture experiments and in vivo administration of antibodies and inhibitors (anti-asialoGM1 Ab, RAGE inhibitors).

Main Results:

• S100A8/A9 expression led to spontaneous regression of established tumors in mice.
• Increased infiltration and activation of Natural Killer (NK) cells within the tumor microenvironment.
• S100A8/A9 enhanced NK cell IFN-γ production via Rae-1/NK group 2D ligand interaction and RAGE signaling.
• Inhibition of RAGE signaling promoted tumor growth, confirming the role of this pathway.

Conclusions:

• S100A8/A9 exhibits potent anti-tumor activity by activating NK cells through the S100A8/A9-RAGE axis.
• This study reveals a novel mechanism of innate immune activation in the tumor microenvironment.
• Findings suggest a potential therapeutic strategy targeting the S100A8/A9-RAGE pathway for cancer treatment.