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.

1. Introduction

The hematopoietic stem cells (HSCs) represent a rare population of quiescent and multi-lineage producing stem cells that persist throughout an individual's lifespan [1]. The presence of external stimuli can rapidly induce partial HSCs to enhance immune cell production, which consequently leads to function attenuation and eventual exhaustion of stem cell [2, 3]. Both acute insults—hemorrhage, infection—and chronic inflammatory states trigger this emergency myelopoiesis, with mature myeloid cells being the dominant product [4–7]. This emergency hematopoiesis is triggered by injuries through both direct and indirect mechanisms [8]. Further investigations have demonstrated that pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α), play important roles in inducing inflammatory response of HSCs [9–15].

Systematic inflammatory stimuli can train HSCs to a long-term myelopoiesis to initiate trained innate immunity [16–18]. In response to pro-inflammatory cytokines, HSCs become active to facilitate rapid myelopoiesis, leading to increased levels of lineage-biased multipotent progenitors (MPPs) and lineage-committed myeloid progenitor cells [19–22]. The MPP compartments indicate an overproduction of megakaryocytic/erythroid-biased MPP2s and granulocyte/macrophage-biased MPP3s, as well as limited presence of lymphoid-biased MPP4s [23, 24]. Although inflammation has been established as a critical inducer of cancer, its impact on HSC function and lineage commitment during tumorigenesis remains unclear.