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

[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.