Characterization of Natural Killer Cell Metabolic and Functional Responses Following Cancer Surgery

Abstract

Surgery undeniably offers cancer patients the best chance of cure. Despite the benefits of surgical intervention, an unintended consequence of surgical stress is profound natural killer (NK) cell suppression. Due to their anti-tumour activity, NK cell dysfunction is a key driver of postoperative metastasis. NK cell activity is closely regulated by metabolic reprogramming in response to stimulation. Here we show that isolated NK cells display widespread intrinsic impairment across their various modes of effector function. We characterized the metabolism of NK cells on postoperative day 1 (POD1) at the pinnacle of their dysfunctional state. The most significant metabolic deficiency was in their ability to perform oxidative phosphorylation (OxPhos), more specifically their maximal respiration and spare respiratory capacity, two major indicators of their ability to respond to a high energetic demand. Their function could not be rescued through nutrient supplementation nor metabolic modulation for more efficient ATP generation. Of the metabolic interventions tested here, feeder cell-based ex vivo expansion was the only approach that partially overcame postoperative suppression, suggesting that comprehensively reprogramming NK cell metabolism before surgery is more effective than attempting to rescue it afterwards. In all, POD1 NK cells demonstrate a profound bioenergetic deficiency, corresponding to an impaired ability to efficiently uptake, metabolize, and channel the corresponding energy produced towards effector function. Given the important role that NK cells play in the anti-tumour immune response, this work addresses a largely unmet need to intervene during this critical window to circumvent postoperative NK cell suppression and ultimately improve outcomes for surgical cancer patients.