Measuring the human immune response to surgery: multiomics for the prediction of postoperative outcomes

Abstract

Purpose of review: Postoperative complications including infections, cognitive impairment, and protracted recovery occur in one-third of the 300 million surgeries performed annually worldwide. Complications cause personal suffering along with a significant economic burden on our healthcare system. However, the accurate prediction of postoperative complications and patient-targeted interventions for their prevention remain as major clinical challenges.

Recent findings: Although multifactorial in origin, the dysregulation of immunological mechanisms that occur in response to surgical trauma is a key determinant of postoperative complications. Prior research, primarily focusing on inflammatory plasma markers, has provided important clues regarding their pathogenesis. However, the recent advent of high-content, single-cell transcriptomic, and proteomic technologies has considerably improved our ability to characterize the immune response to surgery, thereby providing new means to understand the immunological basis of postoperative complications and to identify prognostic biological signatures.

Summary: The comprehensive and single-cell characterization of the human immune response to surgery has significantly advanced our ability to predict the risk of postoperative complications. Multiomic modeling of patients' immune states holds promise for the discovery of preoperative predictive biomarkers, ultimately providing patients and surgeons with actionable information to improve surgical outcomes. Although recent studies have generated a wealth of knowledge, laying the foundation for a single-cell atlas of the human immune response to surgery, larger-scale multiomic studies are required to derive robust, scalable, and sufficiently powerful models to accurately predict the risk of postoperative complications in individual patients.

Figure 1. Balance of proinflammatory and immunosuppressive features in the physiological immune response to surgery.

Alarmins/danger associated molecular patterns (DAMPs) such as HMGB1, ATP, heat shock proteins or hyaluronic acid are released from damaged tissue at the surgery site and recognized by pattern recognition receptors on immune cells. Proinflammatory activity of neutrophils, monocytes, macrophages and dendritic cells with the production of IL-1β, IL-6, IL-8, IL-12, and TNFα is counterbalanced by immunosuppressive processes, such as the induction of Tregs and promotion of Th2 cell immunity, and humoral factors (e.g. IL-10, TGF-β and IL-4).

Figure 2. Pathogenesis of adverse surgical outcomes.

Preoperative factors, such as individual susceptibility due to genetic or lifestyle factors, surgical triggers, such as laparoscopic or open approach, or duration of surgery, influence the degree of tissue damage. Following surgical injury, innate immune cells are activated to secrete cytokines, triggering a cascade of immunological events, such as T_reg/Th17 imbalance, CD8⁺ T cell activation, and HLA-DR sequestration. The nuanced individual differences in each of these pre- and perioperative factors and processes in turn determine whether patients will suffer from postoperative complications.

Figure 3. Multiomic prediction of postoperative outcomes.

Surgical patients are recruited from major medical centers. 1) Whole blood samples are collected and processed for immunome, transcriptome, proteome, and metabolome analysis. 2) Machine learning algorithms applied to individual data layers predict surgical outcomes. The combined multiomic model shows increased predictive power (black) when compared to individual -omics. 3) Patients are stratified into poor or favorable surgical outcomes based on model output.