Single-cell sequencing maps immune changes in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by BCR-ABL1 gene fusion. The immune microenvironment, implicated in relapse and drug resistance, poses significant challenges towards CML treatment. Identifying immune microenvironment changes at the single-cell level may therefore aid in the development of personalized targeted therapies for CML.

In a new study published in the Genes & Diseases journal, researchers from Huazhong Agricultural University, Wuhan University, Chongqing Medical University, Third Military Medical University (Army Medical University), and Huazhong University of Science and Technology conducted multi-level single-cell sequencing to systematically map the bone marrow T cell atlas and the interaction between bone marrow cells and T cells in CML patients.

A comparison of the bone marrow cells from healthy and CML donors showed an increase in the CD8 T cell population along with a decrease in the CD4 T cell population in CML patients, indicating that CML induces enhanced T cell toxicity and an immunosuppressive state. Further analysis of gene expression revealed distinct alterations in both cell populations between the CML and healthy groups.

The authors identified 13 distinct T-cell populations in the bone marrow of healthy and CML patients. Of these, the proportional distribution of CD4 naive, CD8 terminal effector (TE), and CD4 TE cells varied between the CML and healthy bone marrow samples. While the proportion of CD4 naïve T cells in CML patients was significantly lower than in the healthy samples, the CD8 TE cells were significantly increased, indicating that CD8 TE and CD4 naive cells regulate the CML immune microenvironment.

Single-cell T cell sequencing and T cell receptor (TCR) sequencing showed i) a decrease in TCR diversity in CML; ii) an expansion of CD8 TE cells in CML; iii) enrichment of a large number of CD8 TE differential genes in key signaling pathways; and iv) significant changes in CML CD8TE cells, suggesting that a large part of the gene expression changes in CD8 T cells in CML originate from CD8 TE cells.

Further analysis unraveled a complex communication network between T cell subsets and bone marrow microenvironment cells. The proportion of CD8 TE cells was found to significantly correlate with neutrophils, with a significant enrichment of neutrophil-7 subtype, suggesting that this subtype is most associated with CD8 TE cells.

Analysis of the ligand-receptor interaction between neutrophil-7 and CD8 TE cells revealed significant differences in ligand-receptor pairs between CML and healthy patients. The NR3C1_FASLG pair stimulates the expansion of effector T cells, while TNFSF14_TNFRSF14 promotes cytotoxicity. These results suggest a significant interaction between neutrophil-7 and CD8 TE cells and may jointly promote the occurrence and development of CML.

In conclusion, this study utilized multi-level single-cell sequencing to comprehensively characterize the T cell subsets in CML patients, revealing "significant changes in the number and gene expression of T cells, diversity of TCR repertoire, cell-cell communication network, and the potential inter-relationship between bone marrow microenvironment and T cell subsets", thus providing a valuable resource to understand immune changes in CML.