The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer

SIMPLE SUMMARY: The poor prognosis outcome of patients with KRAS mutations (KRAS(mut)) was correlated with an immunosuppressive tumor microenvironment (TME). At the gene expression level and pathway analysis, KRAS(mut) tumor activates TGFβ signaling to reduced proinflammatory and cytokine gene signatures. Spatial profiling in the TME region of KRAS(mut), classified as consensus molecular subtype 3 (CMS3), showed an up-regulation of genes CD40, CTLA4, ARG1, STAT3, IDO, and CD274, associated with immunosuppression in TME. ABSTRACT: Colorectal cancers (CRC) with KRAS mutations (KRAS(mut)) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRAS(mut), focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRAS(mut) in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRAS(wt)). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRAS(mut) and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRAS(mut) in the TME regions of CMS3-classified CRC tissues. CRC patients with KRAS(mut) were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRAS(mut) was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRAS(mut) CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRAS(mut) in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRAS(mut) should consider these transcriptional landscapes.