Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Oxidative stress, induced by reactive oxygen species (ROS), can suppress host immunity.
• Oxidized lipids acting as platelet-activating factor receptor (PAF-R) agonists are implicated in immune suppression.
• Classical chemotherapeutic drugs are known to induce ROS.

Purpose of the Study:

• To investigate if chemotherapeutic drugs activate PAF-R by inducing ROS.
• To determine the mechanism by which chemotherapy might subvert host immunity via PAF-R activation.

Main Methods:

• Administered chemotherapy in vitro, in vivo, and in human subjects with melanoma.
• Structurally characterized PAF-R agonists produced by chemotherapy.
• Utilized a murine melanoma model to assess tumor growth.
• Investigated blocking strategies including antioxidants, COX-2 inhibitors, and regulatory T cell depletion.

Main Results:

• Chemotherapy induced the production of PAF-R agonists, specifically oxidized glycerophosphocholines, in melanoma cells.
• These chemotherapy-induced PAF-R agonists augmented tumor growth in a murine model.
• Tumor growth augmentation was dependent on PAF-R activation.
• Treatment with antioxidants, COX-2 inhibitors, or regulatory T cell depletion blocked this effect.

Conclusions:

• Chemotherapy can activate PAF-R through nonenzymatic generation of oxidized lipids, potentially leading to treatment failure by promoting tumor growth.
• Targeting PAF-R activation presents a novel strategy to enhance the efficacy of chemotherapy.