Alterations in Natural Killer Cells in Colorectal Cancer Patients with Stroma AReactive Invasion Front Areas (SARIFA)

SIMPLE SUMMARY: Our group recently presented Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic biomarker for a poorer outcome in different gastrointestinal cancers, including colon cancer. We hypothesized that the lack of desmoplastic and inflammatory reactions in these carcinomas is based on immunologic alterations. To elucidate this phenomenon, we characterized the peripheral blood lymphocyte subsets and some parts of the local immune responses in colorectal cancer (CRC) patients, in relation to their SARIFA status. Through this, we could observe significant differences between SARIFA-positive and SARIFA-negative CRCs, especially with respect to natural killer (NK) cells. Modifying immune responses by using immunotherapy is already present in clinical routines. Therefore, understanding the basis of SARIFA is crucial for therapeutic strategies, specifically exploiting this new biomarker in CRC patients. This study reveals NK cells as potentially key players in this context, and they should be further investigated. ABSTRACT: Background: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct tumor biology. Considering it is already known that peripheral immune cells are altered in colorectal cancer (CRC) patients, this study aims to investigate the changes in lymphocyte subsets in SARIFA-positive cases and correlate these changes with the local immune response. Methods: Flow cytometry was performed to analyze B, T, and natural killer (NK) cells in the peripheral blood (PB) of 45 CRC patients. Consecutively, lymphocytes in PB, tumor-infiltrating lymphocytes (TILs), and CD56+ and CD57+ lymphocytes at the invasion front and the tumor center were compared between patients with SARIFA-positive and SARIFA-negative CRCs. Results: Whereas no differences could be observed regarding most PB lymphocyte populations as well as TILs, NK cells were dramatically reduced in the PB of SARIFA-positive cases. Moreover, CD56 and CD57 immunohistochemistry suggested SARIFA-status-dependent changes regarding NK cells and NK-like lymphocytes in the tumor microenvironment. Conclusion: This study proves that our newly introduced biomarker, SARIFA, comes along with distinct immunologic alterations, especially regarding NK cells.