Multimodal prehabilitation enhances innate antitumor immunity via NK cell recruitment

BACKGROUND: While the clinical benefits of multimodal prehabilitation in cancer patients are well defined, the underlying immune modulations have not been studied. The objective of this study was to examine how prehabilitation can alter lung cancer immunity. METHODS: Newly diagnosed lung cancer patients were referred to the prehabilitation clinic for preoperative personalized multimodal intervention (exercise training, nutritional optimization, and anxiety reduction) and blood samples were collected at baseline and surgery. Tumor samples were collected at surgery and compared to matched control samples from patients who did not receive prehabilitation. An animal model was used to study prehabilitation and tumor growth kinetics. RESULTS: Twenty-eight lung cancer patients who underwent multimodal prehabilitation were included (McGill University Health Centre Research Ethics Board #2023-9005). After prehabilitation, patient-isolated peripheral blood mononuclear cells (PBMCs) showed significantly increased cytotoxicity against cancer cells (p < 0.0001) and significantly increased circulating natural killer (NK) cells in cohort (p = 0.0290) and paired analyses (p = 0.0312). Compared to matched controls, patients who received prehabilitation had significantly more intra-tumor NK cells (p = 0.0172). In vivo, we observed a significant increase in circulating NK cells (p = 0.0364) and slower tumor growth (p = 0.0396) with prehabilitation. When NK cells were depleted in prehabilitated mice, we observed a decrease in the protective effects of prehabilitation (p = 0.0314) and overall, we observed a significant correlation between circulating NK cells and reduced tumor volume (p = 0.0203, r = -0.5143). CONCLUSIONS: Multimodal prehabilitation may play a role in antitumor immunity by increasing peripheral and tumour-infiltrating NK cells leading to a reduced cancer burden. Future studies on the protective effect of prehabilitation on postoperative immunity should be conducted.