Cara Hatzinger from Rutkowski Lab just received an F31, Investigating the role of TLR5 signaling as a modulator of FLT3 ligand therapeutic efficacy for the treatment of ovarian cancer.
Ovarian cancer is the most fatal gynecological malignancy with most patients developing therapy resistance and recurrence, highlighting the need for more effective therapies. Patients bearing ovarian tumors infiltrated with high frequencies of T cells experience significantly enhanced survival, suggesting the potential for immune therapies. Despite this, therapies such as PD- L1/PD-1 blockade are largely ineffective for ovarian cancer. Because cross presenting cDC1s are fundamental in orchestrating anti-tumor immunity and response to immune therapy, expansion of this immune subset via the DC growth factor fms-like tyrosine kinase receptor 3 ligand (FLT3L) is an attractive strategy for enhancing immune therapy response. Unfortunately, FLT3L therapy has been largely ineffective in clinical trials, with mechanisms leading to the failure unknown. Here, we demonstrate that toll like receptor 5 (TLR5) signaling, the only known ligand for which is bacterial flagellin, mediates failure of FLT3L therapy. Culture of bone marrow cells with FLT3L during chronic exposure to bacterial flagellin promoted differentiation of cDCs away from mature functional cDC1s towards immature monocytes and macrophages expressing high-levels of PD- L1 and having a reduced ability to activate CD8 T cells. Importantly, in vivo expansion of cDC1s using FLT3L therapy in combination with PD-L1 blockade achieved long-term survival in 80% of TLR5 KO mice bearing aggressive orthotopic ovarian tumors. No survival benefit was observed in wild-type mice. These data suggest that TLR5 signaling is orchestrating the failure of FLT3L therapy by driving accumulation of immunosuppressive myeloid cells at the expense of mature cross-presenting cDC1s.