Functional Inactivation of EBV-Specific T-Lymphocytes in Nasopharyngeal Carcinoma: Implications for Tumor Immunotherapy

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated malignancy with high prevalence in Southern Chinese. In order to assess whether defects of EBV-specific immunity may contribute to the tumor, the phenotype and function of circulating T-cells and tumor infiltrating lymphocytes (TILs) were investigated in untreated NPC patients. Circulating naïve CD3+CD45RA+ and CD4+CD25− cells were decreased, while activated CD4+CD25+ T-cells and CD3−CD16+ NK-cells were increased in patients compared to healthy donors. The frequency of T-cells recognizing seven HLA-A2 restricted epitopes in LMP1 and LMP2 was lower in the patients and remained low after stimulation with autologous EBV-carrying cells. TILs expanded in low doses of IL-2 exhibited an increase of CD3+CD4+, CD3+CD45RO+ and CD4+CD25+ cells and 2 to 5 fold higher frequency of LMP1 and LMP2 tetramer positive cells compared to peripheral blood. EBV-specific cytotoxicity could be reactivated from the blood of most patients, whereas the TILs lacked cytotoxic activity and failed to produce IFNγ upon specific stimulation. Thus, EBV-specific rejection responses appear to be functionally inactivated at the tumor site in NPC.

鼻咽癌（Nasopharyngeal carcinoma, NPC）是一种与EB病毒（Epstein-Barr virus, EBV）相关的恶性肿瘤，在华南地区高发。为评估EB病毒特异性免疫缺陷是否参与肿瘤发生，本研究针对未接受治疗的鼻咽癌患者的循环T细胞及肿瘤浸润淋巴细胞（Tumor Infiltrating Lymphocytes, TILs）的表型与功能展开了探究。与健康供者相比，患者体内的初始CD3+CD45RA+循环细胞与CD4+CD25阴性细胞水平降低，而活化CD4+CD25+ T细胞及CD3−CD16+ NK细胞水平升高。患者体内识别LMP1与LMP2中7种HLA-A2限制性表位的T细胞频率较低，且经自体携带EBV的细胞刺激后，该频率仍维持低位。在低剂量白细胞介素2（Interleukin-2, IL-2）作用下扩增的肿瘤浸润淋巴细胞，其CD3+CD4+、CD3+CD45RO+及CD4+CD25+细胞比例升高，且LMP1与LMP2四聚体阳性细胞的频率较外周血高2至5倍。多数患者的血液中可重新激活EB病毒特异性细胞毒性反应，但肿瘤浸润淋巴细胞却缺乏细胞毒性活性，且在特异性刺激后无法分泌干扰素γ（Interferon-γ, IFNγ）。综上，鼻咽癌患者肿瘤部位的EB病毒特异性排斥应答似乎已发生功能性失活。