Identification of T cell dysfunction molecular subtypes and exploration of potential immunotherapy targets in BRAF V600E-mutant colorectal cancer

Abstract

Background: Immunotherapy is an effective treatment for BRAF V600E-mutant colorectal cancer, but currently, only a few benefit from it. Therefore, exploring new immunotherapy strategies is essential. Methods: We obtained RNA sequencing data and clinical information of colorectal cancer patients from the TCGA and GEO databases. The impact of the BRAF V600E mutation on tumor microenvironment characteristics, gene expression, and signaling pathways was evaluated using bioinformatics approaches. Weighted gene co-expression network analysis (WGCNA) were used to identify core genes associated with T cell dysfunction. Consensus clustering was applied for subtype construction. Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) algorithms were employed to filter potential immunotherapy targets. Results: We found that BRAF V600E mutation has a complex impact on the immune profile of colorectal cancer. It increases immune cell infiltration and activates immune-related signaling pathways, yet it also severely restricts T cell function. We subsequently identified 39 core genes associated with T cell dysfunction and constructed subtypes of BRAF V600E colorectal cancer based on their expression profiles. Significant heterogeneity was observed between these subtypes in immune signaling pathway activity, immune infiltration patterns, immune phenotype scores, and mechanisms of resistance to immunotherapy. Ultimately, using machine learning algorithms and bioinformatics validation, we identified IDO1 as a potential immunotherapy targets for BRAF V600E-mutant colorectal cancer. Conclusion: This study constructed novel T cell dysfunction molecular subtypes for BRAF V600E-mutant colorectal cancer and identified IDO1 as a potential immunotherapy target, providing a new strategy for immunotherapy.