Postoperative Changes in Systemic Immune Tolerance Following Major Oncologic versus Minor Maxillofacial Surgery

SIMPLE SUMMARY: Surgical procedures can cause a systemic response of the immune system. This is relevant especially for multimodal tumor therapy in which immunotherapy plays an increasing role. How surgical interventions influence the systemic immune tolerance is not yet well understood. Aim of this study was to monitor changes in postoperative gene expression of cytokines and cellular immune markers in the blood of patients undergoing major maxillofacial tumor surgery compared to minor oral surgical procedures. It could be shown that there was a shift towards temporar systemic immunosuppression in the tumor surgery group compared to minor surgical procedures. The degree of immunosuppression correlated with the duration of surgery with longer procedures caused higher expression of immunosuppressive parameters. However, there were no signs for long-lasting immunosuppression as all analyzed markers approached baseline levels until post-op day 10. The results of this study might be relevant for better timing of neoadjuvant immunotherapy in the multimodal therapy of oral cancer and other malignancies. ABSTRACT: Background: There is increasing evidence of the benefits of adjuvant and neoadjuvant immunotherapy in the treatment of solid malignancies like oral squamous cell carcinoma (OSCC). To optimize (neo-)adjuvant treatment, the systemic immunomodulatory effects of tumor surgery itself need to be considered. Currently, there is little evidence on the immunological effects of major surgery, such as free microvascular flap reconstruction. The current study aims to analyze how and to what extent maxillofacial surgery affects systemic parameters of immune tolerance. Methods: A total of 50 peripheral whole blood samples from patients (Group 1 (G1) = extensive OSCC surgery; Group 2 (G2) = free flap reconstruction without persistent malignant disease; Group 3 (G3) = minor maxillofacial surgery) undergoing surgery were included for real-time quantitative polymerase chain reaction (RT-qPCR) to examine changes in mRNA expression of the biomarkers IL-6, IL-10, FOXP3, and PD-L1. Blood samples were taken immediately before and after surgery as well as on the second, fourth, and tenth postoperative days. Differences in mRNA expression between groups and time points were calculated using statistical tests, including Mann–Whitney U-test and Pearson correlation analysis. Results: Comparing postoperative expression of G1 and G3, there was a significantly higher PD-L1 expression (p = 0.015) in G1 compared to G3 and a significantly lower IL-6 (p = 0.001) and FOXP3 (p = 0.016) expression. Interestingly, IL-10 expression was higher pre- (0.05) and postoperative (p < 0.001) in G1 compared to G3. Additionally, in G1, there was a significant overexpression of IL-10 post-surgery compared to the preoperative value (p = 0.03) and a downregulated expression of FOXP3 between pre- and 2 d post-surgery (p = 0.04). Furthermore, there was a significant correlation between the duration of surgery and the perioperative expression changes of the analyzed biomarkers. As the duration of surgery increased, the expression of IL-10 and PD-L1 increased, and the expression of IL-6 and FOXP3 decreased. Conclusion: Extensive surgery in OSCC patients is associated with a transient shift toward postoperative systemic immune tolerance compared with patients undergoing minor surgery. However, even extensive surgery causes no signs of long-lasting systemic immunosuppression. The degree of immune tolerance that occurred was associated with the duration of surgery. This supports efforts to minimize the duration of surgery.