Distinct NK cell dynamics in SARIFA positive colorectal cancer patients indicate persistent patient-intrinsic immune signatures after tumor resection.

The recently introduced H&E-based biomarker SARIFA (Stroma AReactive Invasion Front Areas) is defined by a direct tumor-adipocyte interaction at the invasion front and is highly predictive for worse outcome in colorectal cancer (CRC). Further analysis revealed an altered lipid metabolism and an immune dysregulation in SARIFA-positive cancers, specifically reduced natural killer (NK) cells. In this study, we investigated whether these lower NK cells in SARIFA-positive patients persist after tumor resection, indicating a patient-intrinsic factor that might contribute to the development of SARIFA-positive tumors. Flow cytometric analysis of NK cells of CRC patients was performed before, 7-10 days and 6 months after resection of the tumors. Using multiplex ELISA (enzyme-linked immunosorbent assay), various inflammatory mediators were examined. 28 SARIFA-negative, 12 SARIFA-positive patients and 27 matched healthy individuals were included. Preoperative NK cell values were previously published and showed significantly lower values for SARIFA-positive patients. Postoperatively NK cells and all their subsets declined in SARIFA-negative patients. Regarding the 6 months follow-up measurements, SARIFA-negative patients showed increasing values of NK cells reaching the initial level, while lower NK-cell levels persisted in SARIFA-positive patients. Multiplex ELISA of inflammatory mediators revealed a postoperative increase of IL5, IL6 and IL8 but no differences between SARIFA-positive and -negative patients. Postoperative measurements of NK cells and different subsets showed a persisting difference between SARIFA-positive and SARIFA-negative patients six months after surgery, which may indicate that patient-intrinsic immunological characteristics are associated with the development of the more aggressive SARIFA-positive tumors.