IFN-γ induces hematopoietic stem cell myelopoiesis through Meis1 in tumor

ABSTRACT: Background Tumors associated overproduction of tissue-damaging myeloid cells and loss of lymphoid cell production were caused by chronic inflammation. Hematopoietic stem cells (HSCs) were the origin of all innate and adaptive immune cells and differentiate through a series of lineage-biased multipotent progenitors (MPPs) dependent on situations. Methods MC38 tumor and Lewis lung cancer models were performed to evaluate HSCs differentiation biased. Through elisa assay and bioinformatic analysis, the key pro-inflammatory cytokine was selected, which promoted myeloid-biased differentiation of HSCs. Next, the main transcription factor was found in tumor induced myeloid-biased differentiation. Finally, HSC-derived myeloid-derived suppressor cells (MDSCs) and impaired T cell functions were measured to evaluate the reason of tumor progression. By targeting myeloid-biased HSCs, Emapalumab was used to suppress tumor progression. Results Here we found HSCs preserved myeloid-biased differentiation in MC38 tumor and Lewis lung cancer models, which reflected extensive properties in tumor models, and was induced by one of pro-inflammatory cytokines, IFN-γ. Transcriptional profiling indicated Meis homeobox 1 (Meis1) was enriched in tumor primed HSCs, and ablation of Meis1 in HSCs prevented HSCs-associated myeloid cell differentiation. HSC-derived MDSCs, which were primary factors, promoted tumor progression. Targeting myeloid differentiated HSCs, combination of anti-PD-1 and Emapalumab, an anti-IFN-γ antibody, inhibited HSC-derived MDSCs and enhanced T cells associated adoptive immune response to suppress tumor progression. Myelodysplastic syndrome (MDS), which was displayed abnormal myeloid cell differentiation induced by hematopoietic failure, was improved by treated with Emapalumab or Meis1 inhibitor. Conclusions These results suggested that targeting HSCs was a new approach to treat tumor, and combination of PD-1 and Emapalumab might serve as a novel therapeutic strategy to improve the response and efficacy of anticancer therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE309030 | GEO | 2026/01/24

REPOSITORIES: GEO