title: Depletion of CD25⁺ T cells from hematopoietic stem cell grafts increases posttransplantation vaccine-induced immunity to neuroblastoma.
abstract: A multifaceted immunotherapeutic strategy that includes hematopoietic stem cell (HSC) transplantation, T-cell adoptive transfer, and tumor vaccination can effectively eliminate established neuroblastoma tumors in mice. In vivo depletion of CD4⁺ T cells in HSC transplantation recipients results in increased antitumor immunity when adoptively transferred T cells are presensitized, but development of T-cell memory is severely compromised. Because increased percentages of regulatory T (Treg) cells are seen in HSC transplantation recipients, here we hypothesized that the inhibitory effect of CD4⁺ T cells is primarily because of the presence of expanded Treg cells. Remarkably, adoptive transfer of presensitized CD25-depleted T cells increased tumor vaccine efficacy. The enhanced antitumor effect achieved by ex vivo depletion of CD25⁺ Treg cells was similar to that achieved by in vivo depletion of all CD4⁺ T cells. Depletion of CD25⁺ Treg cells resulted in elevated frequencies of tumor-reactive CD8 and CD4⁺ T cells and increased CD8-to-Treg cell ratios inside tumor masses. All mice given presensitized CD25-depleted T cells survived a tumor rechallenge, indicating the development of long-term CD8⁺ T-cell memory to tumor antigens. These observations should aid in the future design of immunotherapeutic approaches that promote the generation of both acute and long-term antitumor immunity.
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Jing
authors.forename: Xiaocai
authors.initials: X
authors.lastname: Yan
authors.forename: William H D
authors.initials: WH
authors.lastname: Hallett
authors.forename: Jill A
authors.initials: JA
authors.lastname: Gershan
authors.forename: Bryon D
authors.initials: BD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation
chemical_list: D019496:Cancer Vaccines; C496506:Foxa3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D051543:Hepatocyte Nuclear Factor 3-gamma