Exercise to boost the immune system and optimise immunotherapy responsiveness

Background:
Exercise is known to modulate the immune system, supporting anti-cancer activity. Pancreatic cancer and mesothelioma derive limited benefit from immunotherapy due to their immune-deplete tumour microenvironments (TME). We hypothesised that exercise could enhance immune function and improve immunotherapy responsiveness in these cancers.
Methodology:
Healthy volunteers (n=22) completed a high-intensity cycling session with blood collected pre- and post-exercise. Flow cytometry was used to characterise leucocyte subpopulations, and pancreatic cancer and mesothelioma cell viability, migration, and apoptosis were assessed using pre- and post-exercise serum.
In vivo, C57BL/6 (n=20) and BALB/c (n=24) mice were orthotopically implanted with pancreatic cancer and mesothelioma, respectively. Mice underwent treadmill running and resistance training with anti-Programmed Cell Death Protein 1 (PD1), compared with no exercise and isotype controls. TME immune populations were analysed by flow cytometry and immunofluorescence. Tumour and liver tissues were assessed for necrosis and metastases.
Results:
In healthy volunteers, exercise increased Natural Killer (NK) cells (p<0.0001) and reduced regulatory T cells (Tregs) (p<0.0001). Exercise-conditioned serum decreased cancer cell migration (pancreatic p=0.0313; mesothelioma p=0.0249) and increased apoptosis (pancreatic p=0.0099; mesothelioma p=0.0313).
In mice, exercise/anti-PD1 was feasible from Day 2 post-implantation. In pancreatic cancer, exercise reduced myeloid derived suppressor cells (MDSCs) and Tregs in the TME (p=0.0426 and p=0.0115, respectively), decreased liver metastases, and increased tumour necrosis (p=0.0286 and p=0.0244). Exercise/anti-PD1 also enhanced CD8+PD1+ T cell infiltration in both pancreatic cancer and mesothelioma (p=0.0247 and p=0.0316, respectively).
Conclusions:
Acute aerobic exercise in healthy volunteers promoted systemic cytotoxicity (NK cell expansion) and reduced immune tolerance (Treg suppression). Exercise-conditioned serum exerted direct anti-tumour effects on pancreatic cancer and mesothelioma cells. In mouse models, reduced-intensity exercise elicited anti-tumour activity, and exercise combined with anti-PD1 improved tumour control and reduced metastases in pancreatic cancer. These findings demonstrate the potential of exercise to enhance immunotherapy efficacy across cancer types.