title: Transient Foxp3(+) regulatory T-cell depletion enhances therapeutic anticancer vaccination targeting the immune-stimulatory properties of NKT cells.
abstract: The natural killer T (NKT) cell ligand, alpha-galactosylceramide (α-GalCer), represents a potential adjuvant to boost immunotherapeutic vaccination strategies against poorly immunogenic cancers. The objective of this study was to assess the therapeutic potential of an α-GalCer-loaded tumor-cell vaccine against solid tumors in mice and to enhance the effectiveness of this approach by removing immune suppression associated with the activity of Foxp3(+) regulatory T cells (Tregs). In the B16F10 melanoma model, we show that single vaccination with irradiated, α-GalCer-loaded tumor cells resulted in suppression of established subcutaneous (s.c.) B16F10 tumor growth, which was mediated by NKT cell-dependent IFN-γ production and enhanced in the absence of IL-17 A. Selective depletion of Foxp3(+) Tregs in transgenic DEpletion of REGulatory T cells (DEREG) mice led to significant inhibition of B16F10 tumor growth and enhanced survival of mice receiving vaccination. Short-term elimination of Foxp3(+) Tregs (<7 days) was sufficient to boost vaccine-induced immunity. Enhanced antitumor activity with combination therapy was associated with an increase in systemic NK cell and effector CD8(+) T-cell activation and IFN-γ production, as well as infiltration of effector CD8(+) T cells into the tumor. Overall, these findings demonstrate that transient depletion of Foxp3(+) Tregs constitutes a highly effective strategy to improve the therapeutic efficacy of anticancer vaccination with NKT cell adjuvants.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. s.mattarollo@uq.edu.au
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mattarollo
authors.forename: Kim
authors.initials: K
authors.lastname: Steegh
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Shin
authors.initials: S
authors.lastname: Foong Ngiow
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005699:Galactosylceramides; C098680:Il17a protein, mouse; D020381:Interleukin-17; C493154:alpha-galactosylceramide; D007371:Interferon-gamma