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TLR5 signaling causes dendritic cell dysfunction and orchestrates failure of immune checkpoint therapy against ovarian cancer

ABSTRACT: Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. 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 or CTLA4 blockade , are ineffective for the treatment of ovarian cancer. We demonstrate that for ovarian cancer, Toll-Like Receptor 5 (TLR5) signaling, the only known ligand for which is bacterial flagellin, governs failure of PD-L1 and CTLA4 blockade. Mechanistically, chronic TLR5 signaling on CD11c+ cells in vivo and in vitro impairs the differentiation of functional IL-12-producing XCR1+, CD103+ cDC1 subsets, biasing CD11c+ precursor cells towards myeloid subsets expressing high levels of PD-L1. This culminates in impaired activation of CD8 T cells, reducing CD8 T cell function and ability to persist within the ovarian tumor microenvironment. Expansion of cDC1s in situ using 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 the failure of PD-L1 blockade for ovarian cancer, demonstrating that chronic TLR5 signaling on CD11c+ cells is a barrier limiting the efficacy of checkpoint therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE281417 | GEO | 2025/01/15

REPOSITORIES: GEO

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