Alexander M, Salgaller M L, Celis E, Sette A, Barnes W A, Rosenberg S A, Steller M A
Surgery Branch, National Cancer Institute, Bethesda, MD 20892-1502, USA.
Am J Obstet Gynecol. 1996 Dec;175(6):1586-93. doi: 10.1016/s0002-9378(96)70110-2.
Approximately 90% of squamous carcinomas of the cervix harbor the human papillomavirus and type 16 has been detected in nearly 50% of cases. Recent studies in mice have shown that the human papillomavirus type 16 E7 oncoprotein contains peptide epitopes that are processed and presented in association with a major histocompatibility antigen for recognition by cytolytic T lymphocytes. We investigated whether an epitope from human papillomavirus type 16 E7 could be used to generate specific human cytolytic T lymphocytes in patients with cervical carcinoma.
After radiation therapy, three patients with antigen HLA-A2 and with locally advanced cervical cancer underwent leukapheresis. Epitope-specific cytolytic T lymphocytes were generated from the peripheral blood mononuclear cells by in vitro stimulation with autologous peripheral blood mononuclear cells pulsed with a human papillomavirus type 16 E7, HLA-A2-restricted, synthetic peptide, E7(11-20) (YMLDLQPETT).
In two patients cytolytic T lymphocytes were capable of E7(11-20)-specific, HLA-A2-restricted cytolysis of the peptide-pulsed, HLA-matched, T2 target cell line. Cytolytic T lymphocytes from one of these patients also demonstrated specific cytolysis against the HLA-A2+, HPV-16+ CaSki cervical cancer cell line but did not lyse either HLA-A2+, HPV-16- MS-751 cells or HLA-A2-, HPV-16- HT-3 cells.
These experiments demonstrate that novel cytolytic T lymphocytes that recognize a human papillomavirus type 16 E7 epitope can be generated by using the peripheral blood mononuclear cells from irradiated patients with cervical cancer. In addition, because CaSki cells were specifically lysed by the cytolytic T lymphocytes, these data indicate that the peptide E7(11-20) is endogenously processed and presented on the cell surface of the CaSki cells. The demonstration of epitope-specific lysis of cytolytic T lymphocytes of HPV-16+ cervical cancer cells supports further efforts to develop human papillomavirus peptide-based vaccines or antigen-specific adoptive immunotherapy for the prevention and treatment of cervical carcinoma.
大约90%的子宫颈鳞状细胞癌携带人乳头瘤病毒，近50%的病例中检测到16型。最近在小鼠中的研究表明，16型人乳头瘤病毒E7癌蛋白含有肽表位，这些表位经过加工后与主要组织相容性抗原结合呈递，以供细胞毒性T淋巴细胞识别。我们研究了16型人乳头瘤病毒E7的一个表位是否可用于在子宫颈癌患者中产生特异性人细胞毒性T淋巴细胞。
放疗后，三名具有HLA - A2抗原且患有局部晚期子宫颈癌的患者接受了白细胞去除术。通过用脉冲了16型人乳头瘤病毒E7、HLA - A2限制性合成肽E7(11 - 20)（YMLDLQPETT）的自体外周血单个核细胞进行体外刺激，从外周血单个核细胞中产生表位特异性细胞毒性T淋巴细胞。
在两名患者中，细胞毒性T淋巴细胞能够对脉冲了该肽的、HLA匹配的T2靶细胞系进行E7(11 - 20)特异性、HLA - A2限制性细胞溶解。其中一名患者的细胞毒性T淋巴细胞也对HLA - A2 +、HPV - 16 +的CaSki子宫颈癌细胞系表现出特异性细胞溶解，但不裂解HLA - A2 +、HPV - 16 -的MS - 751细胞或HLA - A2 -、HPV - 16 -的HT - 3细胞。
这些实验表明，通过使用来自接受放疗的子宫颈癌患者的外周血单个核细胞，可以产生识别16型人乳头瘤病毒E7表位的新型细胞毒性T淋巴细胞。此外，由于CaSki细胞被细胞毒性T淋巴细胞特异性裂解，这些数据表明肽E7(11 - 20)在CaSki细胞表面被内源性加工并呈递。HPV - 16 +子宫颈癌细胞的细胞毒性T淋巴细胞表位特异性裂解的证明支持了进一步努力开发基于人乳头瘤病毒肽的疫苗或抗原特异性过继性免疫疗法用于子宫颈癌预防和治疗的研究。
