title: Transient Treg depletion enhances therapeutic anti-cancer vaccination.
abstract: Regulatory T cells (Treg) play an important role in suppressing anti- immunity and their depletion has been linked to improved outcomes. To better understand the role of Treg in limiting the efficacy of anti-cancer immunity, we used a Diphtheria toxin (DTX) transgenic mouse model to specifically target and deplete Treg.
  
  
  
  Tumor bearing BALB/c FoxP3.dtr transgenic mice were subjected to different treatment protocols, with or without Treg depletion and tumor growth and survival monitored.
  
  
  
  DTX specifically depleted Treg in a transient, dose-dependent manner. Treg depletion correlated with delayed tumor growth, increased effector T cell (Teff) activation, and enhanced survival in a range of solid tumors. Tumor regression was dependent on Teffs as depletion of both CD4 and CD8 T cells completely abrogated any survival benefit. Severe morbidity following Treg depletion was only observed, when consecutive doses of DTX were given during peak CD8 T cell activation, demonstrating that Treg can be depleted on multiple occasions, but only when CD8 T cell activation has returned to base line levels. Finally, we show that even minimal Treg depletion is sufficient to significantly improve the efficacy of tumor-peptide vaccination.
  
  
  
  BALB/c.FoxP3.dtr mice are an ideal model to investigate the full therapeutic potential of Treg depletion to boost anti-tumor immunity. DTX-mediated Treg depletion is transient, dose-dependent, and leads to strong anti-tumor immunity and complete tumor regression at high doses, while enhancing the efficacy of tumor-specific vaccination at low doses. Together this data highlight the importance of Treg manipulation as a useful strategy for enhancing current and future cancer immunotherapies.
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Fisher
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Aston
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chee
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Cleaver
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Solin
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Shaokang
authors.initials: S
authors.lastname: Ma
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Lesterhuis
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Ian
authors.initials: I
authors.lastname: Dick
authors.affiliation: British Columbia Cancer Agency Vancouver British Columbia Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holt
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Jenette
authors.initials: J
authors.lastname: Creaney
authors.affiliation: Bioceros Utrecht The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Robinson
authors.affiliation: School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000494:pharmacology*; D000939:Epitopes; D051858:Forkhead Transcription Factors / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D007167:Immunotherapy; D008212:Lymphocyte Depletion; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D010455:Peptides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D004167:Diphtheria Toxin; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D010455:Peptides
keywords:  depletion; Cancer immunotherapy; regulatory T cell; tumor immunology; vaccination