title: c-Met is a novel tumor associated antigen for T-cell based immunotherapy against NK/T cell lymphoma.
abstract: Background:The expression of c-Met and its ligand HGF plays a critical role in cell proliferation and is involved in numerous malignancies. Because c-Met expression and its role in NK/T-cell lymphoma remain unclear, we studied the expression and function of c-Met in NK/T-cell lymphoma cells. In addition, we investigated the possibility that c-Met could function as a tumor-associated antigen for helper T lymphocytes (HTLs).Methods:We evaluated whether HGF and c-Met were expressed in NK/T-cell lymphoma and the capacity of predicted c-Met HTL epitopes to induce antitumor responsesin vitro. In addition, c-Met inhibitor was evaluated for the ability to inhibit TGF-β production in tumor and subsequently increase HTL recognition.Results:c-Met and HGF were expressed in NK/T-cell lymphoma cell lines, nasal NK/T-cell lymphoma specimens and patient serum samples. Moreover, HGF was shown to promote NK/T cell lymphoma (NKTCL) proliferation in an autocrine manner. Furthermore, we have identified three novel c-Met HTL epitopes that were restricted by several HLA-DR molecules. Notably, peptide-induced HTL lines directly recognized and killed c-Met expressing NK/T-cell lymphomas and various epithelial solid tumors. The c-Met specific HTLs could also recognize dendritic cells (DCs) pulsed with c-Met expressing tumor cell lysates. In addition, we observed that c-Met inhibition augmented HTL recognition by decreasing TGF-β production by tumor cells. Lastly, autophagy partly regulated the HTL responses against tumors.Conclusions:We identified novel c-Met HTL epitopes that can elicit effective antitumor responses against tumors expressing c-Met. Our results provide the rationale of combining c-Met targeting therapy and immunotherapy for NKTCLs and epithelial tumors.
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan ; Department of Otolaryngology; Head and Neck Surgery; Asahikawa Medical University ; Asahikawa, Japan ; Cancer Immunology; Inflammation and Tolerance Program; Georgia Regents University Cancer Center ; Augusta, GA USA.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kumai
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohkuri
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Oikawa
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Otolaryngology; Head and Neck Surgery; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.affiliation: Cancer Immunology; Inflammation and Tolerance Program; Georgia Regents University Cancer Center ; Augusta, GA USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.affiliation: Department of Pathology; Asahikawa Medical University ; Asahikawa, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kobayashi
keywords: APCs, antigen presenting cells; CD4+ helper T lymphocytes; DC, dendritic cell; EBV, Epstein-Barr virus; HNSCC, head and neck squamous cell carcinoma; HPLC, high-performance liquid chromatography; HSP, heat shock protein; HTLs, helper CD4+ T cells; L-cell, mouse fibroblast cell line; LDH, lactate dehydrogenase; NK/T cell lymphoma; NKTCL, natural killer/ T cell lymphoma; PBMC, peripheral blood mononuclear cell; PBS, phosphate buffered saline; TCR, T cell receptor; TGF-β; TKI, tyrosine kinase receptor inhibitor; autophagy; c-Met; head and neck squamous cell carcinoma; immunotherapy; major histocompatibility complex class II; tumor antigens