c-Met is a novel tumor associated antigen for T-cell based immunotherapy against NK/T cell lymphoma
c-Met is a novel tumor associated antigen for T-cell based immunotherapy against NK/T cell lymphoma
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DOI：
10.4161/2162402x.2014.976077
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发表时间：
2015-02-01
期刊：
影响因子：
7.2
通讯作者：
Kobayashi, Hiroya
中科院分区：
文献类型：
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作者：
Kumai, Takumi;Matsuda, Yoshinari;Kobayashi, Hiroya
背景：c - met及其配体肝细胞生长因子（HGF）的表达在细胞增殖中起关键作用，并涉及众多恶性肿瘤。由于c - Met在NK/T细胞淋巴瘤中的表达及其作用仍不清楚，我们研究了c - Met在NK/T细胞淋巴瘤细胞中的表达和功能。此外，我们还探讨了c - Met作为辅助性T淋巴细胞（HTLs）相关肿瘤抗原的可能性。
方法：我们评估了HGF和c - Met是否在NK/T细胞淋巴瘤中表达，以及预测的c - Met HTL表位在体外诱导抗肿瘤反应的能力。此外，还评估了c - Met抑制剂抑制肿瘤中转化生长因子 - β（TGF - β）产生并随后增强HTL识别的能力。
结果：c - Met和HGF在NK/T细胞淋巴瘤细胞系、鼻型NK/T细胞淋巴瘤标本以及患者血清样本中均有表达。此外，HGF以自分泌方式促进NK/T细胞淋巴瘤（NKTCL）增殖。而且，我们已经鉴定出三个新的受几种人类白细胞抗原 - DR（HLA - DR）分子限制的c - Met HTL表位。值得注意的是，肽诱导的HTL细胞系可直接识别并杀伤表达c - Met的NK/T细胞淋巴瘤以及各种上皮实体瘤。c - Met特异性HTLs还可识别用表达c - Met的肿瘤细胞裂解物脉冲刺激的树突状细胞（DCs）。此外，我们观察到c - Met抑制通过减少肿瘤细胞产生的TGF - β来增强HTL识别。最后，自噬部分调节了针对肿瘤的HTL反应。
结论：我们鉴定出了新的c - Met HTL表位，其可针对表达c - Met的肿瘤引发有效的抗肿瘤反应。我们的结果为将c - Met靶向治疗与免疫治疗相结合用于NKTCL和上皮肿瘤提供了理论依据。
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-beta 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-b 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.