Ovarian cancer drives TLR5-dependent expansion of myeloid progenitors through systemic ligand dissemination.

Ovarian cancer remains the most lethal gynecologic malignancy, due in part to the establishment of a profoundly immunosuppressive tumor microenvironment (TME). While toll-like receptor 5 (TLR5) signaling has previously been implicated in promoting myeloid cell recruitment to the ovarian TME, source(s) of ligand and systemic effects on hematopoiesis remain poorly understood. Here, we demonstrate that ovarian cancer disrupts gut barrier integrity, leading to systemic translocation of TLR5 ligands into the peritoneum, blood, and bone marrow. This translocation correlates with enhanced expansion of myeloid progenitors in the bone marrow of wild-type (WT) but not TLR5-deficient (TLR5 KO) mice, leading to enhanced accumulation of monocytes and macrophages into the TME. In the bone marrow, direct TLR5 signaling induced expansion of TLR5-expressing granulocyte-monocyte progenitors, a phenotype recapitulated both using an in vitro colony-forming assay and in a mixed bone marrow chimera model. Acute pharmacologic blockade of TLR5 in tumor-bearing mice altered the composition of tumor-associated myeloid populations, reducing the frequency of monocytes and CCR2-expressing macrophages accumulating within the TME of WT mice. These data reveal that chronic TLR5 signaling, driven by tumor-induced loss of gut barrier integrity, promotes expansion of myeloid cells within the bone marrow and is a host-intrinsic mechanism driving accumulation of immature monocytes and macrophages into the TME.