title: Activated human γδ T cells induce peptide-specific CD8+ T-cell responses to tumor-associated self-antigens.
abstract: Specific cellular immunotherapy of cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that recognize tumor-associated self-antigens. Here, we investigated the capacity of human γδ T cells to induce expansion of CD8+ T cells specific for peptides derived from the weakly immunogenic tumor-associated self-antigens PRAME and STEAP1. Coincubation of aminobisphosphonate-stimulated human peripheral blood-derived γδ T cells (Vγ9+Vδ2+), loaded with HLA-A*02-restricted epitopes of PRAME, with autologous peripheral blood CD8+ T cells stimulated the expansion of peptide-specific cytolytic effector memory T cells. Moreover, peptide-loaded γδ T cells efficiently primed antigen-naive CD45RA+ CD8+ T cells against PRAME peptides. Direct comparisons with mature DCs revealed equal potency of γδ T cells and DCs in inducing primary T-cell responses and peptide-specific T-cell activation and expansion. Antigen presentation by γδ T-APCs was not able to overcome the limited capacity of peptide-specific T cells to interact with targets expressing full-length antigen. Importantly, T cells with regulatory phenotype (CD4+ CD25hiFoxP3+) were lower in cocultures with γδ T cells compared to DCs. In summary, bisphosphonate-activated γδ T cells permit generation of CTLs specific for weakly immunogenic tumor-associated epitopes. Exploiting this strategy for effective immunotherapy of cancer requires strategies that enhance the avidity of CTL responses to allow for efficient targeting of cancer.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Altvater
authors.forename: Sibylle
authors.initials: S
authors.lastname: Pscherer
authors.forename: Silke
authors.initials: S
authors.lastname: Landmeier
authors.forename: Sareetha
authors.initials: S
authors.lastname: Kailayangiri
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Heribert
authors.initials: H
authors.lastname: Juergens
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossig
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D000077211:Zoledronic Acid
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D004164:Diphosphonates; D018984:Epitopes, T-Lymphocyte; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D007093:Imidazoles; C404944:PRAME protein, human; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000077211:Zoledronic Acid; D010088:Oxidoreductases; C432763:STEAP1 protein, human