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

Area of Science:

• Immunology
• Oncology
• Translational Medicine

Background:

• Preclinical studies suggest potent immunostimulatory effects of combining toll-like receptor 8 (TLR8) agonism with PD-1 blockade.
• The precise mechanism of action for this combination therapy in humans, particularly in head and neck squamous cell carcinoma (HNSCC), remains largely unknown.

Purpose of the Study:

• To elucidate the combinatory mechanism of action of TLR8 agonism and PD-1 blockade in HNSCC patients.
• To investigate the immune landscape changes induced by dual immune targeting using a pre-operative window of opportunity clinical trial.

Main Methods:

• An open-label, phase 1b clinical trial (NCT03906526) was conducted in HNSCC patients.
• Matched pre- and post-treatment tumor biopsies from the same lesion were analyzed using single-cell RNA sequencing and custom 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 effector genes and cytokines.
• Increased populations of CLEC9A+ dendritic cells and elevated CLEC7A/SYK expression were observed.
• Post-treatment, mature dendritic cells were found adjacent to CD8+ T-cells, with increased cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+ T-cell populations in responders.
• All patients exhibited increased tertiary lymphoid structures (TLSs).

Conclusions:

• This study provides critical insights into the in vivo mechanism of action for combining TLR8 agonism with PD-1 blockade in HNSCC.
• The findings highlight the therapy's ability to enhance innate and adaptive immune responses, paving the way for optimized immune-based cancer treatments.