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Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1

Daniel A Ruiz-Torres1,2,3,4, Jillian F Wise2,3,4,5,6, Brian Yinge Zhao1

  • 1Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United States.

Frontiers in Immunology
|December 19, 2024
PubMed

Insights

Combining toll-like receptor 8 (TLR8) agonism with PD-1 blockade boosts innate immune responses in head and neck cancer patients. This dual therapy increases dendritic cells and T-cells, potentially enhancing anti-tumor immunity.

Area of Science:

  • Immunology
  • Oncology
  • Translational Medicine

Background:

  • The combination of toll-like receptor 8 (TLR8) agonism and PD-1 blockade shows promise in preclinical studies for cancer immunotherapy.
  • However, the precise mechanisms driving this combination's efficacy in human patients, particularly in head and neck squamous cell carcinoma (HNSCC), remain largely unexplored.

Purpose of the Study:

  • To elucidate the combined mechanism of action of TLR8 agonism and PD-1 blockade in HNSCC patients.
  • To investigate the immunological changes induced by this dual therapy in a pre-operative window of opportunity clinical trial.

Main Methods:

  • An open-label, phase 1b clinical trial (NCT03906526) was conducted in HNSCC patients.
  • Matched tumor biopsies before and after treatment were analyzed using single-cell RNA sequencing and multiplex staining.
  • Data were compared with a previous cohort treated with anti-PD-1 monotherapy.

Main Results:

  • Dual TLR8 agonism and anti-PD-1 blockade led to significant upregulation of innate immune genes and cytokines.
  • Increased populations of CLEC9A+ dendritic cells and elevated CLEC7A/SYK expression were observed.
  • Post-treatment, mature dendritic cells were found near CD8+ T-cells, with increased cytotoxic T-lymphocyte densities, expanded CXCL13+ CD8+ T-cell populations, and enhanced tertiary lymphoid structures (TLSs) in responders.

Conclusions:

  • This study reveals that combining TLR8 agonism with PD-1 blockade enhances innate immune activation and promotes adaptive immune responses in HNSCC.
  • The findings provide critical insights into the immunomodulatory effects of this combination therapy, paving the way for optimized cancer treatment strategies.
Keywords:
cancercheckpoint blockadedendritic cellsimmune responseimmunotherapy

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