title: Induction of HLA-DP4-restricted anti-survivin Th1 and Th2 responses using an artificial antigen-presenting cell.
abstract: OBJECTIVE
  In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4(+) T-cell responses against survivin in cancer patients.
  
  
  METHODS
  We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4(+) T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4(+) T cells were determined.
  
  
  RESULTS
  We first determined previously unknown DP4-restricted CD4(+) T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4-aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti-survivin CD4(+) T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC.
  
  
  CONCLUSIONS
  DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4(+) and CD8(+) T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, USA.
authors.forename: Makito
authors.initials: M
authors.lastname: Tanaka
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.forename: Osamu
authors.initials: O
authors.lastname: Imataki
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D059868:HLA-DP beta-Chains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D010750:Phosphoproteins / Q000276:immunology; D000077022:Survivin; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000276:immunology; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D018984:Epitopes, T-Lymphocyte; D059868:HLA-DP beta-Chains; D007136:Immunoglobulins; D051034:Inhibitor of Apoptosis Proteins; D007371:Interferon-gamma; D015847:Interleukin-4; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D000077022:Survivin; D014763:Viral Matrix Proteins; D000097802:CD83 Antigen; C107489:BIRC5 protein, human; C056284:HLA-DPw4 antigen; C065418:cytomegalovirus matrix protein 65kDa