An Investigation of Chromatin Dynamics in Natural Killer Cells After Tumour Resection to Identify Therapeutic Targets Against Postoperative Anti-Tumour Immune Dysfunction

Abstract

Tumour resection is critical for improving the overall survival of patients with solid malignancies, yet surgery paradoxically generates an environment that favours residual disease, in part through widespread immunosuppression. Natural killer (NK) cells are key mediators of anti-tumour immunity and their postoperative dysfunction has been intricately linked to cancer recurrence, though its molecular basis remains unclear. Here, we demonstrate that circulating NK cells from cancer patients are globally hyporesponsive following surgery, and that this dysfunction persists despite removal from the immunosuppressive postoperative milieu. Multiomic profiling suggests a coordinated state of genome remodeling, metabolic suppression, and dysregulated protein homeostasis. Central to this dysfunctional state was a subpopulation of NK cells characterized by a loss of accessibility around some effector gene promoters, alongside an increase in the predicted activity of heat shock factors (HSF), despite reduced overall translation and protein aggregation. Simultaneously, the predicted activities of activator protein 1 (AP-1) transcription factors were aberrantly lost in these stressed cells. Critically, to determine if genome remodeling can be prevented, and subsequently correlated with the prevention of NK cell dysfunction, we developed a novel ex vivo model in which healthy donor NK cells are added to postoperative blood and assayed for their effector functions. Preliminary experiments identified BET inhibitors and PKC agonists that prevented healthy donor NK cell dysfunction, but not endogenous NK cell dysfunction in postoperative blood. Altogether, these findings define a distinct stress signature underlying postoperative NK cell dysfunction and suggest that prevention, rather than reversal of the epigenomic remodeling, is necessary to improve postoperative NK cell anti-tumour immunity.