title: EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy.
abstract: BACKGROUND
  Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy.
  
  
  METHODS
  We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition.
  
  
  RESULTS
  Among several predicted peptide epitopes, EGFR875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875-889 epitope could be detected in the blood of HNSCC patients. EGFR875-889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875-889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.
  
  
  CONCLUSIONS
  We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875-889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy.
authors.affiliation: 1] Department of Pathology, Asahikawa Medical University, Asahikawa, Japan [2] Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumai
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuda
authors.forename: K
authors.initials: K
authors.lastname: Oikawa
authors.forename: N
authors.initials: N
authors.lastname: Aoki
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Harabuchi
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D045744:Cell Line, Tumor; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D019169:Jurkat Cells; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D000077195:Squamous Cell Carcinoma of Head and Neck; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D010446:Peptide Fragments; C512478:EGFR protein, human; D066246:ErbB Receptors
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