title: Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of 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 patients with HNSCC.
  
  
  METHODS
  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 patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/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 intratumoral 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). In addition, the concentration of blood CD8(+) T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory 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 antitumor immunity.
  
  
  CONCLUSIONS
  Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8(+) T cells in a dose-dependent fashion.
authors.affiliation: Department of Otolaryngology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Donald T
authors.initials: DT
authors.lastname: Weed
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Vella
authors.affiliation: Department of Public Health Sciences and Sylvester Biostatistics and Bioinformatics Core Resource, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Isildinha M
authors.initials: IM
authors.lastname: Reis
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: De la Fuente
authors.affiliation: Department of Pathology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez
authors.affiliation: Department of Otolaryngology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Zoukaa
authors.initials: Z
authors.lastname: Sargi
authors.affiliation: Department of Otolaryngology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Ronen
authors.initials: R
authors.lastname: Nazarian
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland.|Milton J. Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Califano
authors.affiliation: Oncology Department, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.affiliation: Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.
authors.forename: Paolo
authors.initials: P
authors.lastname: Serafini
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002243:Carbolines / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000276:immunology; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000473:pathology; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5