title: Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC).
  
  
  METHODS
  We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC).
  
  
  RESULTS
  Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04).
  
  
  CONCLUSIONS
  These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Milton J Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland. jcalifa@jhmi.edu iborrell@jhmi.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Zubair
authors.initials: Z
authors.lastname: Khan
authors.affiliation: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Noonan
authors.affiliation: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rudraraju
authors.affiliation: Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Steven
authors.initials: S
authors.lastname: Goodman
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Gourin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland. Milton J Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Ha
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland. Milton J Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Carole
authors.initials: C
authors.lastname: Fakhry
authors.affiliation: Milton J Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland. Oncology Department, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Marshall
authors.initials: M
authors.lastname: Levine
authors.affiliation: Oncology Department, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Mei
authors.initials: M
authors.lastname: Tang
authors.affiliation: Oncology Department, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neuner
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Richmon
authors.affiliation: Milton J Dance Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors.forename: Ray
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Koch
authors.affiliation: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Marur
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: Paolo
authors.initials: P
authors.lastname: Serafini
authors.affiliation: Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland. jcalifa@jhmi.edu iborrell@jhmi.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002243:Carbolines / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000276:immunology; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5