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.Conclusion: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.

Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

“…This LMP1 For example, epidermal growth factor receptor (EGFR) is a TAA that is highly expressed in head and neck cancer and only slightly expressed in normal tissues such as the colon [36]. We have shown that EGFR-reactive T-cells are present in head and neck cancer patients without any clinical symptoms of autoimmune diseases, supporting the notion that TAA-reactive T-cells mainly recognize tumors and not healthy tissues [37]. Thus, TAA-derived epitopes are candidates for peptide vaccines.…”

Radiotherapy plus EGFR inhibitors: synergistic modalities

“…A study by Kumai et al offers promising evidence in this respect, showing that the EGFR875-889 peptide induced effective anti-tumor CD4 T-cell responses against cancer that expressed EGFR. The authors thus suggest that the peptide could serve as an effective cross-reacting epitope, inducing responses to other HER family members and to the c-Met antigen [68]. Another encouraging phase Ib study aimed at evaluating the effectiveness of using cetuximab with motolimod, a small-molecule TLR-8 agonist that activates myeloid dendritic cells, monocytes, and natural killer cells.…”

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

“…47 To augment HLA-G expression in tumor cells, the tumor cells were treated with 5-AZA and IFNg as described above. The expression of HLA-DR molecules on the tumor cell surface was evaluated by flow cytometry using anti-HLA-DR mAb conjugated with FITC (BD PharMingen, #55581).…”

“…47 The production level of IFNg by PBMCs derived from patients with breast or lung cancer was evaluated by ELISA (BD PharMingen, #555142). The institutional ethics committee approved this study protocol (approval number 14029).…”