Perioperative arginine prevents metastases by accelerating natural killer cell recovery after surgery

Profound natural killer (NK) cell suppression after cancer sur-gery is a main driver of metastases and recurrence, for which there is no clinically approved intervention available. Surgical stress is known to cause systemic postoperative changes that negatively modulate NK cell function including the expansion of surgery-induced myeloid-derived suppressor cells (Sx-MDSCs) and a marked reduction in arginine bioavailability. In this study, we determine that Sx-MDSCs regulate systemic arginine levels in the postoperative period and that restoring arginine imbalance after surgery by dietary intake alone was sufficient to significantly reduce surgery-induced metastases in our preclinical murine models. Importantly, the effects of perioperative arginine were dependent upon NK cells. Although perioperative arginine did not prevent immediate NK cell immunoparalysis after surgery, it did accelerate their return to preoperative cytotoxicity, interferon gamma secretion, and activating receptor expression. Finally, in a cohort of patients with colorectal cancer, postoperative argi-nine levels were shown to correlate with their Sx-MDSC levels. Therefore, this study lends further support for the use of peri-operative arginine supplementation by improving NK cell re-covery after surgery.

Automated summary

This study demonstrates that Sx-MDSCs regulate postoperative arginine levels, and restoring arginine imbalance through dietary intake significantly reduces surgery-induced metastases in preclinical murine models. The effects of perioperative arginine supplementation depend on NK cells.