Single-Cell Roadmap of Immune Cell Response in Chronic Myeloid Leukemia

Only half of chronic myeloid leukemia (CML) patients in deep molecular remission are able to maintain treatment free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation. Identifying predictive markers for TFR remains a key issue. The immunological control or eradication of TKI insensitive leukemic stem cells may contribute to successful cessation, as recent work has demonstrated that differences in immune cell compositions can be associated with better probability of TFR. In order to understand the precise immunological changes in CML, we profiled over 170,000 cells from 25 CML samples from different clinical phases (untreated, during TKI therapy and after TKI cessation) using single-cell RNA and T cell receptor (TCR) αβ sequencing (scRNA+TCRab-seq). We profiled both CD45+ sorted peripheral blood samples (n=20) and CD34+ sorted bone marrow samples (n=5). To understand antigen-specific responses, we profiled TCRs specific to tumor-antigen PR1 (n=12) and compared these to unsorted TCRβ-sequenced samples from CML (n=137) and healthy donors (n=786). To understand the distinctive immunological features in CML, we compared the immune system in CML (n=20) to those in other hematological and solid malignancies profiled with scRNA+TCRab-seq (n=9). We discovered NK cells to be the most unique feature in CML, as NK CD56dim cells were more abundant in CML patients (Padj