Identification and validation of a CD4+ T cell-related prognostic model to predict immune responses in stage III-IV colorectal cancer.

Background: CD4⁺ T cells play an indispensable role in anti-tumor immunity and shaping tumor development. We sought to explore the characteristics of CD4⁺ T cell marker genes and construct a CD4⁺ T cell-related prognostic signature for stage III-IV colorectal cancer (CRC) patients.

Method: We combined scRNA and bulk-RNA sequencing to analyze stage III-IV CRC patients and identified the CD4⁺ T cell marker genes. Unsupervised cluster analysis was performed to divide patients into two clusters. The LASSO and multivariate Cox regression were performed to establish a prognostic-related signature. RT-qpcr and immunofluorescence staining were performed to examine the expression of ANXA2 in CRC tissue.

Result: We found a higher infiltration abundance of activated memory CD4⁺ T cells was associated with improved prognosis in stage III-IV CRC patients. Patients were divided into two subgroups with distinct clinical and immunological behaviors based on CD4⁺ T cell marker genes. And then a prognostic signature consisting of six CD4⁺ T cell marker genes was established, which stratified patients into high- and low-risk groups. Immune spectrum showed that the low-risk group had higher immune cell infiltration than the high-risk group. Furthermore, the risk score of this signature could predict the susceptibility of stage III-IV CRC patients to immune checkpoint inhibitors and chemotherapy drugs. Finally, we validated that ANXA2 was enriched in Tregs and was associated with infiltration of Tregs in CRC tumor microenvironment.

Conclusion: The CD4⁺ T cell-related prognostic signature established in the study can predict the prognosis and the response to immunotherapy in stage III-IV CRC patients. Our findings provide new insights for tumor immunotherapy of advanced CRC patients.