OVARIAN cancer remains the deadliest cancer affecting the female reproductive system. Despite significant advances in immunotherapy, current checkpoint blockade therapies, such as PD-L1/PD-1 or CTLA4 inhibitors, have shown limited success in treating this malignancy. Emerging research now identifies Toll-Like Receptor 5 (TLR5) signalling as a crucial factor in this failure.
Patients with ovarian tumours infiltrated by high frequencies of T cells generally exhibit better survival outcomes. However, the effectiveness of immunotherapies designed to revitalise these tumour-associated T cells is hindered by a previously unrecognised mechanism linked to TLR5 signalling. TLR5 is a receptor known to be activated by bacterial flagellin, and its chronic activation within the tumour microenvironment appears to impair key immune responses.
Mechanistically, persistent TLR5 signalling on CD11c+ immune cells disrupts the differentiation of functional dendritic cells, particularly IL-12-producing XCR1+CD103+ conventional type 1 dendritic cells (cDC1). Instead of fostering effective anti-tumour immunity, CD11c+ precursor cells are biased toward myeloid subsets that highly express PD-L1. This shift weakens CD8+ T-cell activation, reducing their ability to function and persist within the ovarian tumour microenvironment.
The study further demonstrates that overcoming this barrier is possible. Expanding cDC1 populations within the tumour using FLT3L (Fms-like tyrosine kinase 3 ligand) in conjunction with PD-L1 blockade resulted in a significant survival benefit, but only in TLR5-deficient mice. In contrast, in the presence of active TLR5 signalling, this combined approach remained ineffective.
These findings highlight a host-intrinsic mechanism responsible for the failure of PD-L1 blockade in ovarian cancer. Chronic TLR5 activation within CD11c+ cells limits the efficacy of checkpoint therapy, revealing a potential target for improving treatment outcomes in ovarian cancer patients. Future therapeutic strategies may need to consider modulating TLR5 signalling to enhance the success of immunotherapy in this disease.
Katie Wright, EMJ
Reference
McGinty MT, Putelo AM, Kolli SH, et al. TLR5 signaling causes dendritic-cell dysfunction and orchestrates failure of immune checkpoint therapy against ovarian cancer. Cancer Immunol Res. 2025;DOI:10.1158/2326-6066.CIR-24-0513.
