Genomic Analysis Defines Increased Circulating, Leukemia-Induced Macrophages That Promote Immune Suppression in Mouse Models of FGFR1-Driven Leukemogenesis

TL;DR

This study shows that leukemia in mice causes immune suppression by increasing specific macrophages, and blocking these macrophages improves survival.

Contribution

The study identifies leukemia-induced macrophages as key immune suppressors and shows that targeting them improves survival in mouse models.

Findings

Leukemia in mice increases circulating macrophages derived from Ly6CHi M-MDSC and monocytic populations.

Leukemia-induced macrophages upregulate stress and inflammation genes like Hspa1a, Hspa1b, and Nfkbia.

Blocking macrophages with GW2580 restores immune surveillance and improves survival in leukemic mice.

Abstract

The development of FGFR1-driven stem cell leukemia and lymphoma syndrome (SCLL) in mouse models is accompanied by an increase in highly heterogenous myeloid derived suppressor cells (MDSCs), which promote immune evasion. To dissect this heterogeneity, we used a combination of CyTOF and scRNA-Seq to define the phenotypes and genotypes of these MDSCs. CyTOF demonstrated increased levels of circulating macrophages in the peripheral blood of leukemic mice, and flow cytometry demonstrated that these macrophages were derived from Ly6CHi M-MDSC as well as the Ly6CInt and Ly6CLow monocytic populations. Consistently, scRNA-Seq analysis demonstrated the accumulation of non-classical monocytes (ncMono) during leukemia progression, which also express macrophage markers. These leukemia-induced macrophages show continuous transcriptional reprogramming during leukemia progression, with the upregulation of cellular stress response genes Hspa1a and Hspa1b and inflammation-related gene Nfkbia. Trajectory analysis revealed a transition from classical monocytes (cMono) to ncMono, and potential genes orchestrating this transition process have been identified. Furthermore, T-cell suppression assays demonstrated the immune suppressive abilities of leukemia-induced circulatory macrophages. Targeting these macrophages with the GW2580 CSF1R inhibitor leads to restored immune surveillance and improved survival. Overall, we demonstrate that circulating macrophages are responsible, at least in part, for the immune suppression in SCLL leukemia models, and targeting macrophages in this system improves the survival of leukemic mice.

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