New insight into the response mechanism of arsenic in treating acute promyelocytic leukemia

In this study, researchers from Harbin Medical University conducted a comprehensive characterization of the tumor microenvironment in APL patients undergoing arsenic trioxide (ATO) therapy using single-cell sequencing. Initially, APL cells were classified into distinct subpopulations, revealing several groups with diverse characteristics. Notably, one LSC-like subpopulation, marked by high expression of stemness-related genes and a pronounced LSC signature, was identified as the root of differentiation arrest in APL. This subpopulation was largely eradicated following treatment, offering novel insights into how ATO affects APL cells.

As is well known, lymphocytes, including T cells, NK cells, and B cells, are key components of antitumor immunity. The researchers subsequently analyzed other immune components, with a particular focus on lymphocytes. They found that ATO treatment induced the enrichment of a CD8 T cell subpopulation, termed the CD8 ISG subtype, characterized by elevated expression of interferon-stimulated genes. Further analyses indicated that ATO treatment significantly enhanced both the effector functions and TCR clonotype expansion of this subtype. Additionally, through a constructed co-expression network, they revealed further functional characteristics of this CD8 subpopulation. For example, beyond its association with ISG genes, this subpopulation also exhibited signatures related to myeloid differentiation, arsenic response, and immune activation.

Subsequently, the researchers observed that NK cells in APL patients exhibited a dysfunctional state, which was largely reversed following ATO therapy. Notably, an activated NK cell subpopulation associated with the ATO response was identified, characterized by pronounced NFκB signaling and inflammatory activation. In addition, ATO treatment was found to remodel the distribution of immunoglobulin proteins, as revealed by integrated scRNA-seq and scBCR-seq analyses. Finally, the study elucidated the complex cellular communication network and identified the LT pathway as a key signaling axis mediating interactions between the CD8 ISG subtype and NK NFκB subtype with APL cells, contributing to myeloid differentiation and immune activation.

In conclusion, this study mapped the rewired hematopoietic lineage and notably identified two lymphocyte subpopulations associated with the response to ATO treatment: the CD8 ISG T cells and the NK NFκB cells, which provides a deeper insight into the underlying mechanisms in the context of ATO therapy for APL patients.

The authors acknowledge funding from the National Key Research and Development Program of China; the National Natural Science Foundation of China; the Natural Science Foundation of Heilongjiang Province (Key Program) and the project of scientific research business expenses of provincial research institutes.

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