Purpose: Myeloid-derived-suppressor-cells (MDSCs) and regulatory T-cells (Treg) play a key role in the progression of Head and Neck squamous cell carcinoma (HNSCC). Based on our preclinical data demonstrating that Phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor Tadalafil, can revert tumor-induced immunosuppression and promote tumor-immunity in HNSCC patients. Experimental Design: First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which HNSCC patients undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with Tadalafil 10mg/day, 20mg/day or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+T-cell reactivity to tumor antigens were evaluated before and after treatment. Results: MDSCs were characterized in HNSCC and their intra-tumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (p<0.05). Additionally, the concentration of blood CD8+T-cells reactive to autologous tumor-antigens significantly increased after treatment (p<0.05). Tadalafil immune-modulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect anti-tumor immunity. Conclusions: Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in HNSCC patients by lowering MDSCs and Tregs and increasing tumor specific CD8+T-cells in a dose dependent fashion.
- Received July 3, 2014.
- Revision received September 2, 2014.
- Accepted September 3, 2014.
- Copyright © 2014, American Association for Cancer Research.