title: Circulating CD4+ T cells that produce IL4 or IL17 when stimulated by melan-A but not by NY-ESO-1 have negative impacts on survival of patients with stage IV melanoma.
abstract: OBJECTIVE
  We initially observed that the presence of circulating NY-ESO-1- and/or Melan-A-specific T cells in patients with stage IV melanoma was significantly associated with prolonged survival. Here, we report the ways in which the phenotypes and functions of these T cells differentially affect survival in patients preselected for NY-ESO-1 and/or Melan-A reactivity.
  
  
  METHODS
  We assayed functional antigen-reactive T cells recognizing NY-ESO-1 and/or Melan-A after in vitro stimulation using overlapping peptide pools. After restimulation, we assayed six cytokines simultaneously by intracellular cytokine staining. This allowed us to analyze the functional antigen response of both CD4(+) and CD8(+) T cells at the single-cell level.
  
  
  RESULTS
  We observed that NY-ESO-1 stimulated mainly CD4(+) T cells, whereas Melan-A more often stimulated CD8(+) T cells. NY-ESO-1 reactivity was not associated with an additional impact on survival, whether CD4(+) T cells, CD8(+) T cells, or both types of T cells were responding. In contrast, recognition of Melan-A by CD4(+) T cells was associated with reduced survival in our cohort of patients preselected for NY-ESO-1 and/or Melan-A reactivity (that is, in patients with exceptionally long survival). We further observed a negative effect on survival in patients with CD4(+) T cells producing IL4 and IL17 upon Melan-A stimulation. Their prognosis was comparable to patients without any Melan-A reactivity.
  
  
  CONCLUSIONS
  The nature and prognostic impact of specific T-cell responses is different according to targeted antigen. Independent from phenotype and functional aspects, NY-ESO-1 reactivity is associated with good prognosis. In terms of Melan-A, antigen-specific CD8(+) but not CD4(+) responses are associated with prolonged survival. Clin Cancer Res; 20(16); 4390-9. ©2014 AACR.
authors.affiliation: Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology; Department of Immunology, University of Tübingen, Tübingen; henning.zelba@klinikum.uni-tuebingen.de.
authors.forename: Henning
authors.initials: H
authors.lastname: Zelba
authors.affiliation: Division of Dermatooncology, Department of Dermatology, University Medical Center;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.affiliation: Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology;
authors.forename: Alexander
authors.initials: A
authors.lastname: Martens
authors.affiliation: Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology;
authors.forename: Evelyna
authors.initials: E
authors.lastname: Derhovanessian
authors.affiliation: Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology;
authors.forename: Jithendra Kini
authors.initials: JK
authors.lastname: Bailur
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital;
authors.forename: Christina
authors.initials: C
authors.lastname: Kyzirakos
authors.affiliation: Division of Dermatooncology, Department of Dermatology, University Medical Center;
authors.forename: Annette
authors.initials: A
authors.lastname: Pflugfelder
authors.affiliation: Division of Dermatooncology, Department of Dermatology, University Medical Center;
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Eigentler
authors.affiliation: Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy;
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giacomo
authors.affiliation: Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy;
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.affiliation: Nijmegen Centre for Molecular Life Sciences (NCMLS); Department of Nuclear Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands; and.
authors.forename: Erik H J G
authors.initials: EH
authors.lastname: Aarntzen
authors.affiliation: Nijmegen Centre for Molecular Life Sciences (NCMLS);
authors.forename: Jolanda
authors.initials: J
authors.lastname: de Vries
authors.affiliation: Department of Dermatology, University Medical Center, Essen, Germany;
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Department of Dermatology, University Medical Center, Essen, Germany;
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Skin Cancer Research Group, School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Australia.
authors.forename: Petra
authors.initials: P
authors.lastname: Büttner
authors.affiliation: Division of Dermatooncology, Department of Dermatology, University Medical Center;
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Internal Medicine II, Section for Transplantation Immunology and Immunohematology;
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020381:Interleukin-17 / Q000097:blood* / Q000276:immunology; D015847:Interleukin-4 / Q000097:blood* / Q000276:immunology; D058965:MART-1 Antigen / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D020381:Interleukin-17; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008565:Membrane Proteins; D015847:Interleukin-4