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

Abstract Background The role of inflammation-induced myeloid-biased hematopoiesis in driving resistance to immune checkpoint blockade (ICB) is recognized, yet the intricate mechanisms through which tumors orchestrate it are not fully defined. Methods MC38 tumor and Lewis lung cancer models were performed to evaluate hematopoietic stem cells (HSCs) differentiation biased. Key pro-inflammatory cytokines implicated in this process were screened through ELISA assay and bioinformatic analysis. Subsequent mechanistic investigations identified the central transcription factor governing tumor-induced myeloid-biased differentiation of HSCs. To demonstrate the functional impact on antitumor immunity, we quantified HSC-derived myeloid-derived suppressor cells (MDSCs) and assessed their suppressive effects on T cell function. Furthermore, the therapeutic potential of targeting this axis was evaluated using Emapalumab, an anti-IFN-γ antibody, to determine whether suppressing myeloid-biased HSCs could enhance the antitumor effects of ICB. Results Here, we found HSCs exhibit a persistent myeloid-biased differentiation phenotype in MC38 tumor and Lewis lung cancer models, which was induced by the 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. The resulting HSC-derived MDSCs were identified as key factors of tumor progression. Therapeutic targeting of the myeloid differentiation axis with a combination of anti-PD-1 antibody and Emapalumab, an anti-IFN-γ antibody inhibited HSC-derived MDSCs production and enhanced T cells-mediated adaptive immunity to suppress tumor progression. Conclusions Our results highlight HSC-directed therapy as a novel approach for cancer treatment. Combining anti-PD-1 with Emapalumab potently enhances the response to ICB, offering a promising strategy to achieve superior and durable anticancer efficacy.