Indoleamine 2, 3-Dioxygenase 1 and CD8 Expression Profiling Revealed an Immunological Subtype of Colon Cancer With a Poor Prognosis

BACKGROUND: The Immunoscore method, based on the distribution of the quantification of cytotoxic and memory T cells, provides an indicator of tumor recurrence for colon cancer. However, recent evidence has suggested that immune checkpoint expression represents a surrogate measure of tumor-infiltrating T cell exhaustion, and therefore may serve as a more accurate prognostic biomarker for colon cancer. Indoleamine 2, 3-dioxygenase 1 (IDO1), a potent immunosuppressive molecule, has been strongly associated with T-cell infiltration, but it lacks universal prognostic significance among all of the cancer subtypes. Our aim was to elucidate the prognostic significance of the combination of IDO1 and CD8A expression in colon cancer. METHODS: Gene expression and clinical survival data were analyzed using The Cancer Genome Atlas (TCGA) data set and validated using NCBI Gene Expression Omnibus (NCBI-GEO) cohort. Hierarchical clustering, functional enrichment analyses, and immune infiltration analysis were applied to evaluate the distinctive immune statuses in colon cancer risk subgroups stratified by IDO1 and CD8A expression. Moreover, Multivariate Cox regression analysis and Receiver Operating Characteristic (ROC) analyses were conducted to determine the prognostic value of IDO1/CD8A stratification. The IDO1/CD8A classifier may be suitable for use in the prediction of cancer development. It was validated via an in vivo murine model. RESULTS: The stratification analysis demonstrated that the colon cancer subtype with the CD8A(high)IDO1(high)* tumor resulted in the worst survival despite high levels of CD8 infiltrates. Its poor prognosis was associated with high levels of immune response, checkpoint genes, and Th1/IFN-γ gene signatures, regardless of CMS classification. Moreover, the IDO1/CD8A stratification was identified as an independent prognostic factor of overall survival (OS) and a useful predictive biomarker in colon cancer. In vivo data revealed the CD8A(high)IDO1(high) group showed strong correlations with late-stage metastasis of colon carcinoma cells and upregulation of immune checkpoints. CONCLUSIONS: The findings indicate that the proposed IDO1/CD8A stratification has exact and independent prognostic implications beyond CD8 T cell alone and CMS classification. As a result, it may represent a promising tool for risk stratification in colon cancer and improve the development of immunotherapies for patients with colon cancer in the future.