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TLR5 Signaling Causes Dendritic Cell Dysfunction and Orchestrates Failure of Immune Checkpoint Therapy against

Mitchell T McGinty1, Audrey M Putelo1, Sree H Kolli1

  • 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia.

Cancer Immunology Research
|February 11, 2025
PubMed

Insights

Toll-like receptor 5 (TLR5) signaling hinders effective ovarian cancer immunotherapy. Blocking PD-L1/PD-1 or CTLA4 fails because TLR5 signaling impairs anti-tumor T cells, offering a new therapeutic target.

Area of Science:

  • Immunology
  • Oncology
  • Microbiology

Background:

  • Ovarian cancer is a leading cause of cancer death in women.
  • Tumor-infiltrating T cells correlate with better survival in ovarian cancer patients.
  • Current immunotherapies like PD-L1/PD-1 and CTLA4 blockade are often ineffective for ovarian cancer.

Purpose of the Study:

  • To investigate the mechanism behind the failure of PD-L1 and CTLA4 blockade in ovarian cancer.
  • To identify the role of Toll-like receptor 5 (TLR5) signaling in immunotherapy resistance.
  • To explore potential strategies for overcoming immunotherapy resistance in ovarian cancer.

Main Methods:

  • Utilized mouse models of ovarian cancer with and without TLR5 signaling.
  • Analyzed immune cell populations, including dendritic cells and T cells, using flow cytometry.
  • Investigated the impact of TLR5 signaling on dendritic cell differentiation and function.
  • Assessed the efficacy of combining Flt3L-Ig with PD-L1 blockade in TLR5-deficient mice.

Main Results:

  • Chronic TLR5 signaling, activated by bacterial flagellin, was found to govern the failure of PD-L1 and CTLA4 blockade in ovarian cancer.
  • TLR5 signaling impaired the differentiation of functional IL-12-producing XCR1+CD103+ conventional type 1 dendritic cells.
  • This impairment led to the expansion of PD-L1-expressing myeloid cells, reduced CD8+ T cell activation, and diminished anti-tumor immunity.
  • Combining Flt3L-Ig with PD-L1 blockade improved survival in TLR5 knockout mice, but not in the presence of TLR5 signaling.

Conclusions:

  • Chronic TLR5 signaling on CD11c+ cells is a key host-intrinsic mechanism responsible for the inefficacy of PD-L1 blockade in ovarian cancer.
  • Targeting TLR5 signaling or enhancing conventional type 1 dendritic cell function may overcome immunotherapy resistance.
  • This study identifies a critical barrier to checkpoint therapy in ovarian cancer and suggests a novel therapeutic approach.

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