Transient Treg depletion enhances therapeutic anti-cancer vaccination.

Autor: Fisher SA; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Aston WJ; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Chee J; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Khong A; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Cleaver AL; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Solin JN; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Ma S; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Lesterhuis WJ; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Dick I; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Holt RA; British Columbia Cancer Agency Vancouver British Columbia Canada., Creaney J; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Boon L; Bioceros Utrecht The Netherlands., Robinson B; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia., Lake RA; School of Medicine and PharmacologyUniversity of Western Australia, QEII Medical CentreNedlandsWestern AustraliaAustralia; National Research Centre for Asbestos Related DiseasesQEII Medical CentreNedlandsWestern AustraliaAustralia.
Jazyk: angličtina
Zdroj: Immunity, inflammation and disease [Immun Inflamm Dis] 2016 Nov 21; Vol. 5 (1), pp. 16-28. Date of Electronic Publication: 2016 Nov 21 (Print Publication: 2017).
DOI: 10.1002/iid3.136
Abstrakt: Introduction: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Databáze: MEDLINE
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