The effects of cytomegalovirus reactivation and systemic inflammation on adaptive NK cells in ovarian cancer patients

Abstract

Objectives: Identify if CMV reactivation allows for expansion of a special adaptive (natural killer) NK cell population with enhanced ability to kill ovarian cancer and determine if in a setting of increased inflammation (high CRP levels), this inflammatory response decreases the immunologic effect on tumor cells with an overall decrease in NK cell function and in cytokines necessary to activate immunogenic attacks. Methods: Serum (n=20 benign, 36 cancer) and ascites samples (n=18) collected in a prospective study at the time of surgery for HGSOC were evaluated for CMV and inflammation. CMV status and systemic inflammation were measured by immunoassay for CMV immunoglobulin G (IgG), dPCR for CMV DNA and C-reactive protein (CRP). Samples were categorized as reactive or non-reactive for CMV and positive or negative for CRP (≤10, >10 mg/L). Additionally, 32 HGOSC samples were measured for IL-6. Data were analyzed using SAS 9.4 (Cary, NC). P-values ≤ 0.05 were considered statistically significant. Flow cytometry was used to evaluate adaptive NK cells and assess cytotoxicity. Results: CMV reactivated patients had increased adaptive NK cells (NKG2C+CD57+) in serum and ascites compared to CMV non-reactived patients (p=0.043, p=0.077). In the serum, patients that were positive for CMV reactivation and were CRP negative had increased adaptive NK cells compared to patients that were CMV reactive and CRP positive. Elevated IL-6 levels in the serum and ascites correlated with CRP positive samples. There was no correlation between adaptive NK levels in blood and ascites in benign patient samples (r2=-0.03, p=0.46), however there was a positive correlation between adaptive NK levels in blood and ascites of ovarian cancer patient samples (r2=0.37 p=0.002). Adaptive NK cell levels correlate in CMV IgG positive cancer samples (r2=0.55, p=0.003), however CMV IgG negative samples did not correlate (r2=-0.04, p=0.45). Download : Download high-res image (45KB) Download : Download full-size image Conclusions: These findings suggest CMV reactivation increases the prevalence of adaptive NK cells in ovarian cancer patients.