EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy

T. Kumai, Y. Matsuda, K. Oikawa, N. Aoki, S. Kimura, Y. Harabuchi, E. Celis, H. Kobayashi

Research output: Contribution to journalArticle

27 Citations (Scopus)

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, EGFR 875-889 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 EGFR 875-889 epitope could be detected in the blood of HNSCC patients. EGFR 875-889 -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 EGFR 875-889 -reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.Conclusion:We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR 875-889 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.

Original languageEnglish (US)
Pages (from-to)2155-2166
Number of pages12
JournalBritish Journal of Cancer
Volume109
Issue number8
DOIs
StatePublished - Oct 15 2013

Fingerprint

Helper-Inducer T-Lymphocytes
Epidermal Growth Factor Receptor
Immunotherapy
T-Lymphocytes
Epitopes
T-Lymphocyte Epitopes
Neoplasms
Peptides
Therapeutics
Carcinoma, squamous cell of head and neck
HLA-DR4 Antigen
Peptide T
Aptitude
Blocking Antibodies
HLA-DR Antigens
Head and Neck Neoplasms
Protein-Tyrosine Kinases
Dendritic Cells

Keywords

  • CD4 helper T lymphocytes
  • epidermal growth factor receptor (EGFR)
  • head and neck squamous cell carcinoma (HNSCC)
  • immunotherapy
  • major histocompatibility complex class II
  • tumour antigens

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kumai, T., Matsuda, Y., Oikawa, K., Aoki, N., Kimura, S., Harabuchi, Y., ... Kobayashi, H. (2013). EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. British Journal of Cancer, 109(8), 2155-2166. https://doi.org/10.1038/bjc.2013.577

EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. / Kumai, T.; Matsuda, Y.; Oikawa, K.; Aoki, N.; Kimura, S.; Harabuchi, Y.; Celis, E.; Kobayashi, H.

In: British Journal of Cancer, Vol. 109, No. 8, 15.10.2013, p. 2155-2166.

Research output: Contribution to journalArticle

Kumai, T, Matsuda, Y, Oikawa, K, Aoki, N, Kimura, S, Harabuchi, Y, Celis, E & Kobayashi, H 2013, 'EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy', British Journal of Cancer, vol. 109, no. 8, pp. 2155-2166. https://doi.org/10.1038/bjc.2013.577
Kumai, T. ; Matsuda, Y. ; Oikawa, K. ; Aoki, N. ; Kimura, S. ; Harabuchi, Y. ; Celis, E. ; Kobayashi, H. / EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. In: British Journal of Cancer. 2013 ; Vol. 109, No. 8. pp. 2155-2166.
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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, EGFR 875-889 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 EGFR 875-889 epitope could be detected in the blood of HNSCC patients. EGFR 875-889 -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 EGFR 875-889 -reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.Conclusion:We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR 875-889 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.",
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AU - Kumai, T.

AU - Matsuda, Y.

AU - Oikawa, K.

AU - Aoki, N.

AU - Kimura, S.

AU - Harabuchi, Y.

AU - Celis, E.

AU - Kobayashi, H.

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N2 - 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, EGFR 875-889 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 EGFR 875-889 epitope could be detected in the blood of HNSCC patients. EGFR 875-889 -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 EGFR 875-889 -reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.Conclusion:We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR 875-889 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.

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KW - major histocompatibility complex class II

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