Immune Landscape Refines the Classification of Colorectal Cancer With Heterogeneous Prognosis, Tumor Microenvironment and Distinct Sensitivity to Frontline Therapies

The immune microenvironment has profound impacts on the initiation and progression of colorectal cancer (CRC). Therefore, the goal of this article is to identify two robust immune subtypes in CRC, further provide novel insights for the underlying mechanisms and clinical management. In this study, two CRC immune subtypes were identified using the consensus clustering of immune-related gene expression profiles in the meta-GEO dataset (n = 1,198), and their reproducibility was further verified in the TCGA-CRC dataset (n = 638). Subsequently, we characterized the immune escape mechanisms, gene alterations, and clinical features of two immune subtypes. Cluster 1 (C1) was defined as the "immune cold subtype" with immune cell depletion and deficiency, while cluster 2 (C2) was designed as the "immune hot subtype", with abundant immune cell infiltration and matrix activation. We also underlined the potential immune escape mechanisms: lack of MHC molecules and defective tumor antigen presentation capacity in C1, increased immunosuppressive molecules in C2. The prognosis and sensitivity to 5-FU, Cisplatin and immunotherapy differed between two subtypes. According to the two immune subtypes, we developed a prognosis associated risk score (PARS) with the accurate performance for predicting the prognosis. Additionally, two nomograms for overall survival (OS) and disease-free survival (DFS) were further constructed to facilitate clinical management. Overall, our research provides new references and insights for understanding and refining the CRC.