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Immunotherapy has achieved positive clinical responses in various cancers. However, in advanced colorectal cancer (CRC), immunotherapy is challenging because of the deterioration of T-cell exhaustion, the mechanism of which is still unclear. In this study, we depicted CD8 +  T-cell developmental trajectories and characterized the pre-exhausted T cells isolated from CRC patients in the scRNA-seq data set using a dynamic network biomarker (DNB). Moreover,  CCT6A  identified by DNB was a biomarker for pre-exhausted T-cell subpopulation in CRC. Besides,  TUBA1B  expression was triggered by  CCT6A  as DNB core genes contributing to CD8 +  T cell exhaustion, indicating that core genes serve as biomarkers in pre-exhausted T cells. Remarkably, both  TUBA1B  and  CCT6A  expressions were significantly associated with the overall survival of COAD patients in the TCGA database ( p  = 0.0082 and  p  = 0.026, respectively). We also observed that cellular communication between terminally differentiated exhausted T cells and pre-exhausted T cells contributes to exhaustion. These findings provide new insights into the mechanism of T-cell exhaustion and provide clue for targeted immunotherapy in CRC.

Dynamic Network Biomarker of Pre-Exhausted CD8+ T Cells Contributed to T Cell Exhaustion in Colorectal Cancer