(The) prognostic value of the tumor microenvironment and its clinical application in advanced colorectal cancer patients with synchronous or metachronous metastases

Abstract

Introduction: Recently, the range of targeted therapy has expanded and the tumor microenvironment has been suggested as a probable target of a novel systemic targeted therapy. Furthermore, the Immunoscore (IS) system, which quantifies one of the tumor microenvironmental factors, tumor-infiltrating lymphocyte (TIL), has been recently suggested to be a useful prognostic biomarker, especially in colorectal cancer (CRC). We aimed to investigate the clinical significance of microenvironmental factors, which include microvessel density (MVD), lymphatic vessel density (LVD), cancer-associated fibroblasts (CAF), and tumor-infiltrating immune cells, in relationship to tumor location of advanced CRC. Methods: A total of 196 advanced CRC patients with synchronous or metachronous metastases who were treated at Seoul National University Bundang Hospital were enrolled in this study. The tumor microenvironments including MVD, LVD, CAF, and tumor-infiltrating immune cells were confirmed using immunohistochemistry (IHC) and a computerized image analysis system. To evaluate the regional heterogeneity of these properties, tissue from three sites (the center [CT] and invasive margin [IM] of the primary cancer and a distant metastasis [DM]) were examined. The IS score, which is based on the combination scoring data from several tumor-infiltrating immune cells in respective tumor regions, was assessed for all patients. Results: The tumor microenvironmental factors showed heterogeneity with respect to the tumor location. Patients with low MVD and LVD in their CT had worse outcomes and patients with few CAFs in their IM and DM had a lower survival rate. Patients with high TIL in their primary or metastatic tumor had better outcomes. A high density of tumor-associated macrophages (TAMs) was also associated with poorer outcomes. When the patients were assessed using the IS system, a higher score was significantly correlated with better patient outcomes. In multivariate analysis, the IS model, which encompasses the results of TILs in DM, was an independent prognostic factor (p = 0.012). Conclusions: Microenvironmental factors are distributed heterogeneously with respect to the tumor location in CRC patients and they have a significant effect on patient outcome. IS is a reproducible method and is useful for predicting the survival of advanced CRC patients. This new immunoscoring model, including CD3- and CD8-positive cells in distant metastases, can independently predict overall survival in advanced CRC patients.