Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Mol Ther. 2022 Oct 5;30(10):3270-3283. doi: 10.1016/j.ymthe.2022.05.024. Epub 2022 May 26.
Profound natural killer (NK) cell suppression after cancer surgery 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 arginine levels were shown to correlate with their Sx-MDSC levels. Therefore, this study lends further support for the use of perioperative arginine supplementation by improving NK cell recovery after surgery.
癌症手术后自然杀伤 (NK) 细胞的深度抑制是转移和复发的主要驱动因素，但目前临床上尚无批准的干预措施。众所周知，手术应激会导致全身性术后变化，从而负调控 NK 细胞功能，包括手术诱导的髓系来源抑制细胞 (Sx-MDSC) 的扩增和精氨酸生物利用度的显著降低。在这项研究中，我们确定 Sx-MDSC 在术后期间调节全身精氨酸水平，并且通过饮食摄入单独恢复手术后的精氨酸失衡足以显著减少我们的临床前小鼠模型中的手术诱导转移。重要的是，围手术期精氨酸的作用取决于 NK 细胞。尽管围手术期精氨酸不能防止手术后 NK 细胞的即刻免疫麻痹，但它确实加速了它们恢复术前的细胞毒性、干扰素 γ 分泌和激活受体表达。最后，在结直肠癌患者队列中，术后精氨酸水平与 Sx-MDSC 水平相关。因此，这项研究通过改善手术后 NK 细胞的恢复，进一步支持使用围手术期精氨酸补充。
