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 responses in 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.
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.