Abstract
Ovarian cancer is the seventh most common and eighth leading cause of cancer death in women globally. Diagnosis is challenging due to vague symptoms and a lack of effective screening methods, leading to late-stage diagnosis and poor prognosis. Despite progress in surgical techniques and chemotherapy regimens, overall survival improvements remain modest. New approaches such as immunotherapy have shown limited success despite their effectiveness in other cancers. Patients bearing ovarian tumors infiltrated with high frequencies of T cells are associated with a greater survival probability. However, therapies to revitalize tumor-associated T cells, such as PD-L1/PD-1 and CTLA-4 blockade, are ineffective for the treatment of ovarian cancer. Thus, there is a demand to understand why immunotherapy is ineffective against ovarian cancer.
A study from a parent lab found that Toll-Like Receptor 5 (TLR5) signaling impacts inflammation, anti-tumor immunity, and the clinical outcome of ovarian cancer patients. However, the influence of TLR5 signaling on immunotherapy remained unexplored. In this dissertation, we demonstrate that in late-stage murine ovarian cancer models, TLR5 signaling, the only known ligand for which is bacterial flagellin, leads to failure of immune therapy. Mechanistically, we demonstrate that chronic TLR5 signaling on dendritic cells impairs the differentiation of functional cDC1 subsets within the tumor microenvironment (TME). Instead, chronic TLR5 signaling biases precursor cells towards myeloid-associated subsets expressing high levels of PD-L1. This culminates in impaired activation of CD8 T cells, reducing CD8 T cell function and persistence within the ovarian tumor microenvironment. Expansion of cDC1s in situ using FMS-related Tyrosine Kinase 3 ligand (FLT3L) in combination with PD-L1 blockade achieved significant survival benefit, but only in TLR5 KO mice, whereas no benefit was observed in the presence of TLR5 signaling. Thus, we identify a host-intrinsic mechanism leading to failure of immune therapy for ovarian cancer, demonstrating that chronic TLR5 signaling on DCs is a barrier limiting the efficacy of immune therapy. Clinically, roughly 7.5% of the general population harbors a TLR5 SNP that diminishes TLR5 signaling and is associated with increased long-term survival for ovarian cancer patients. Therefore, patients who express the TLR5 SNP may immediately benefit from anti-PDL1 therapy, and those without the SNP, TLR5 antagonism.
