High expression of CCL3/CCL4/CCL5/CCR5 promotes exhausted CD8+ T cells terminal differentiation and is associated with poor prognosis in pediatric B-ALL patients.

This study aims to identify differentially upregulated ligand-receptor interactions between B-ALL cells and exhausted CD8⁺ T cells and to develop a multivariate Cox regression model for predicting the overall survival of pediatric B-ALL patients based on CCL3/CCL4/CCL5 expression levels. Pediatric B cell-acute lymphoblastic leukemia (B-ALL) is a hematopoietic malignancy. T cell exhaustion has an important impact on the prognosis of leukemia. The interaction between tumor cells and T cells can influence the degree of T cell exhaustion. However, the effects of B-ALL cells on exhausted T cell subpopulations and how the interaction influences the prognosis of B-ALL patients remain unclear. Single-cell RNA sequencing (scRNA-Seq) data from pediatric B-ALL patients were downloaded from GEO. Cell interaction analysis identified ligand-receptor pairs between B-ALL cells and exhausted CD8⁺ T cell. To confirm the function of CCL3/CCL4/CCL5/CCR5 in prognosis prediction, quantitative real-time polymerase chain reaction (qRT-PCR) was employed. We further developed an innovative stratified model that integrates CCL3, CCL4, and CCL5 through multi-Cox regression. Clustering of scRNA-Seq data revealed an increased proportion of exhausted CD8⁺ T cells in relapsed B-ALL, especially terminal exhausted CD8⁺ T cells (CD8_Ex), with increased exhaustion and decreased proliferation scores. Moreover, the CCL3/CCL4/CCL5-CCR5 axis was upregulated in interactions between B-ALL cells and terminal CD8_Ex. Transcriptome data from 221 pediatric B-ALL samples revealed that high CCL3/CCL4/CCL5/CCR5 levels correlate with low overall survival (OS). A multivariate Cox regression model incorporating CCL3/CCL4/CCL5 predicted prognoses. Finally, a model based on the adult B-ALL patients from our center also accurately predicted prognoses. We report for the first time the crucial role of the CCL3/CCL4/CCL5-CCR5 axis in the differentiation of terminal exhausted CD8⁺ T cells in B-ALL. High expression of CCL3, CCL4, CCL5, and CCR5 correlates with poor prognosis in B-ALL, suggesting potential biomarkers and therapeutic targets.