The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production

Abstract

Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, though the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is interferon regulatory factor-8 (IRF8), which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. Here, we showed that: 1) tumor growth was associated with a selective expansion of newly defined IRF8lo granulocytic progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8−/− GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling

“…The role of the immune-suppressive myeloid compartment in favoring progression of disease in MM has been demonstrated both in experimental 35,36,55,56 and clinical models [57][58][59][60][61] , however this is the first study reporting changes in human HDNs during an hematological malignancy, developed in the bone marrow, where the tumor cells share the same site with myeloid progenitors. Our findings clearly indicate that the combination of phenotypic changes (increased CD64 and Arg-1) and function (reduced phagocytosis and increased immune-suppression) occurring in MM-HDN overlap with those described for G-MDSC in MM, in line with recent reports in the field 62 , while HDN in healthy subjects do not have immunosuppressive features. Key MDSC genes and canonical signaling pathways are activated along tumor progression, as recently demonstrated in murine cancer models, where a consensus set of 817 genes, involved in myeloid cell recruitment and angiogenesis, was identified 63 .…”

An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

“…IRF8 regulates myeloid cell differentiation through repressing granulocyte development and promoting differentiation of monocytic cells such as dendritic cells and macrophages (39)(40)(41)(42)(43). IRF8 functions in hematopoietic cell differentiation and activation have since been extended to other hematopoietic cells, including B, NK, and T cells (25,31,41,(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). However, IRF8 functions in T cells are apparently tissue-and disease-specific (25,30,38,46,53,57).…”

Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment

“…Advanced cancer is associated with a myeloid bias characterized by increased frequencies of circulating granulocyte-monocyte progenitors that are skewed toward differentiating into granulocytes (21). Tumor-derived factors, such as G-CSF, GM-CSF, and IL-6, drive this myeloid bias (22) and result in a circulating and tumor-infiltrating MDSC population that accelerates tumor progression by suppressing T cell responses and releasing factors that promote metastasis. Cui et al (23) found that MDSC in EOC triggered acquisition of stem cell-like features in cancer cells and increased metastatic potential, and they found that myeloid cell (CD33 + ) accumulation was associated with worse outcomes.…”