Resveratrol Enhances CAR NK Cell Function in Cellular Immunotherapy of Non-Hodgkin Lymphoma

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Resveratrol (RSV) is a polyphenol with anticancer properties, but its clinical use is limited.
• Chimeric antigen receptor (CAR) natural killer (NK) cell therapy shows promise for refractory cancers.
• The impact of RSV on CAR NK cell therapy is currently unknown.

Purpose of the Study:

• To investigate the role of RSV in enhancing CAR NK cell immunotherapy.
• To evaluate RSV's effects on CAR NK cell function, metabolism, and anti-cancer activity.
• To explore the underlying mechanisms of RSV-mediated CAR NK cell augmentation.

Main Methods:

• Preconditioning of anti-CD19 CAR NK cells with RSV.
• Assessment of CAR NK cell resistance to oxidative stress and metabolic activity.
• In vitro cytotoxicity assays against non-Hodgkin lymphoma (NHL) cells.
• In vivo studies using NHL xenograft models with RSV-treated CAR NK cells.
• Mechanistic studies involving nuclear factor erythroid 2-related factor 2 (NRF2) pathway analysis.

Main Results:

• RSV preconditioning improved CAR NK cell resistance to oxidative stress and enhanced their metabolic function.
• RSV-treated CAR NK cells exhibited increased cytotoxicity against NHL cells and augmented cytokine secretion.
• In vivo, RSV extended CAR NK cell tissue residency and improved therapeutic efficacy in NHL xenografts.
• RSV-adjuvanted CAR NK therapy significantly reduced tumor burden and improved survival in mice.
• NRF2 was identified as a key mediator of RSV's beneficial effects on CAR NK cells.

Conclusions:

• Resveratrol acts as a potent adjuvant to improve CAR NK cell therapy for non-Hodgkin lymphoma.
• RSV enhances CAR NK cell function, metabolism, and in vivo efficacy through the NRF2 pathway.
• This study presents a translatable strategy using RSV to overcome limitations in CAR NK cell therapy and improve cancer treatment outcomes.