Dissection of Immune Profiles in Microsatellite Stable and Low Microsatellite Instability Colon Adenocarcinoma by Multiomics Data Analysis

BACKGROUND: Although microsatellite instability (MSI) is an indicator for active immunotherapy response, only 15% of colon adenocarcinoma (COAD) patients are with MSI. An investigation into the immune profiles in low MSI (MSI-L) and microsatellite stable (MSS) COAD remains lacking, whereas such exploration may provide new insights into COAD immunity. METHODS: We hierarchically clustered MSI-L/MSS COAD based on the enrichment levels of 28 immune signatures to identify its immune-specific subtypes. We also comprehensively compared molecular and clinicopathologic profiles among these subtypes. RESULTS: We identified three immune subtypes of MSI-L/MSS COAD (IM-H, IM-M, and IM-L), which had high, medium, and low immune signature scores, respectively. We demonstrated that this subtyping method was reproducible and predictable by analyzing five different datasets, including four bulk tumor datasets and one single-cell dataset. IM-H was characterized by high immunity, high stemness, strong potential of proliferation, invasion and metastasis, epithelial-mesenchymal transition, elevated expression of oncogenic pathways, low tumor purity, low intratumor heterogeneity (ITH), genomic instability, inferior response to chemotherapy, and unfavorable prognosis. IM-M was characterized by the highest ratio of immunostimulatory to immunosuppressive signatures, the best response to chemotherapy, and favorable prognosis. IM-L was characterized by low immunity, high tumor purity, high ITH, and genomic stability. CONCLUSION: The immune-specific subtyping of MSI-L/MSS COAD may provide new insights into the tumor immunity as well as clinical implications for immunotherapy of the COAD patients who lack MSI.