Abstract
Ovarian cancer is the most lethal gynecologic malignancy, with late-stage presentation and limited survival benefit from current therapies. Diagnosis is hindered by vague symptoms and a lack of effective screening, while surgical cytoreduction and chemotherapy offer only modest long-term improvements. Immunotherapy has been transformative in other cancers, yet checkpoint blockade has failed to improve outcomes for ovarian cancer patients. A defining feature of this disease is the immunosuppressive tumor microenvironment (TME), where myeloid-derived cells accumulate and restrict antitumor immunity. However, the systemic mechanisms that drive their expansion remain poorly understood.
In this dissertation, we demonstrate that ovarian cancer disrupts gut barrier integrity, permitting systemic dissemination of Toll-like receptor 5 (TLR5) ligands, the only known ligand for which is bacterial flagellin. These ligands accumulate in the peritoneum, circulation, and bone marrow, where chronic TLR5 signaling expands granulocyte–monocyte progenitors and biases differentiation toward monocytic lineages. Mechanistically, this process culminates in increased recruitment of Ly6C⁺CCR2⁺ monocytes and macrophages into the ovarian TME, populations associated with immune suppression and poor prognosis. Using competitive bone marrow chimeras, we show that this phenotype is dependent on TLR5 expression within the hematopoietic compartment, indicating that progenitor intrinsic TLR5 signaling drives myeloid skewing in vivo. In parallel, colony-forming assays demonstrate that purified flagellin directly stimulates bone marrow progenitors to form granulocyte–macrophage colonies, confirming that progenitors themselves respond to TLR5 engagement. Pharmacologic blockade of TLR5 in tumor bearing mice reduces monocyte and macrophage accumulation in the TME, further implicating this pathway in shaping tumor-associated myelopoiesis.
