Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and...

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Natural killer (NK) cells are crucial for anti-tumor immunity.
• Dysfunctional NK cells are observed in various cancers.
• Immune checkpoints, like PD-1, regulate T cell activity and are implicated in cancer progression.

Purpose of the Study:

• To investigate the expression and role of programmed cell death protein 1 (PD-1) on NK cells in digestive cancers.
• To evaluate the therapeutic potential of blocking the PD-1/PD-L1 pathway in NK cell-mediated anti-tumor immunity.

Main Methods:

• Flow cytometry was used to assess PD-1 expression on peripheral and tumor-infiltrating NK cells from patients with digestive cancers.
• In vitro assays were performed to analyze the effects of PD-1/PD-L1 blockade on NK cell function (cytokine production, degranulation, apoptosis).
• PI3K/AKT signaling pathway activation was examined in NK cells.
• In vivo studies using xenograft models in nude mice were conducted, with and without NK cell depletion, to assess the impact of PD-1 blockade on tumor growth.

Main Results:

• High PD-1 expression was found on NK cells in patients with esophageal, liver, colorectal, gastric, and biliary cancers.
• Increased PD-1 expression correlated with poorer survival in esophageal and liver cancer patients.
• Blocking PD-1/PD-L1 signaling in vitro enhanced NK cell effector functions (cytokine production, degranulation) and reduced apoptosis.
• PD-1/PD-L1 signaling inhibited NK cell activation by suppressing the PI3K/AKT pathway.
• In vivo, PD-1 blockade significantly suppressed tumor xenograft growth, an effect dependent on NK cells.

Conclusions:

• PD-1 acts as an inhibitory regulator of NK cell function in digestive cancers.
• PD-1 blockade demonstrates therapeutic potential for enhancing NK cell-based anti-tumor immunotherapy in digestive cancers.