Kubuschok Boris, Neumann Frank, Breit Rainer, Sester Martina, Schormann Claudia, Wagner Claudia, Sester Urban, Hartmann Frank, Wagner Mathias, Remberger Klaus, Schilling Martin, Pfreundschuh Michael
Department of Internal Medicine I , University of Saarland Medical School, Homburg/Saar, Germany.
Clin Cancer Res. 2006 Feb 15;12(4):1365-72. doi: 10.1158/1078-0432.CCR-05-1672.
Mutated p21 ras proteins (muRas) are present in approximately 90% of pancreatic adenocarcinomas and express mutants which can function as cancer-specific antigens. To evaluate the frequency and magnitude of the natural T-cell response against muRas in 19 HLA-A2-positive patients with muRas-positive pancreatic carcinomas, antigen-experienced T lymphocytes in fresh peripheral blood mononuclear cells were shown by IFN-gamma enzyme-linked immunospot using muRas peptides (5-21) that encompass both HLA class I (HLA-A2)- and class II-restricted (HLA-DRB1) epitopes. Six of 19 patients (32%) were found to have a specific T-cell response against individual mutation-specific ras(5-21) but not against other ras mutations or wild-type ras. In contrast, none of 19 healthy subjects had T cells specifically secreting IFN-gamma (P = 0.004). The T-cell response consisted of both CD8(+) and CD4(+) T cells but was dominated by CD8 T cells in three of four patients. MuRas(5-14) and muRas(6-14) were shown to specifically induce CD8(+) T-cell mediated cytotoxicity against HLA-A2-positive, muRas-bearing pancreatic carcinoma cells. The T-cell response was not correlated with prognostic or clinical variables such as tumor-node-metastasis status, stage, or survival. In conclusion, a natural T-cell response against muRas proteins that could be exploited for immunostimulatory therapeutic approaches has been shown in a significant proportion of patients with pancreatic cancer.
突变型p21 ras蛋白（muRas）存在于约90%的胰腺腺癌中，并表达可作为癌症特异性抗原发挥作用的突变体。为评估19例HLA - A2阳性且muRas阳性胰腺癌患者中针对muRas的天然T细胞反应的频率和强度，利用包含HLA I类（HLA - A2）和II类（HLA - DRB1）表位的muRas肽（5 - 21），通过IFN - γ酶联免疫斑点法检测新鲜外周血单个核细胞中具有抗原经验的T淋巴细胞。19例患者中有6例（32%）被发现对个别突变特异性的ras(5 - 21)有特异性T细胞反应，但对其他ras突变或野生型ras无反应。相比之下，19名健康受试者中无一例有特异性分泌IFN - γ的T细胞（P = 0.004）。T细胞反应由CD8(+)和CD4(+) T细胞组成，但在4例患者中有3例以CD8 T细胞为主。已证明MuRas(5 - 14)和muRas(6 - 14)可特异性诱导CD8(+) T细胞介导的针对HLA - A2阳性、携带muRas的胰腺癌细胞的细胞毒性。T细胞反应与肿瘤 - 淋巴结 - 转移状态、分期或生存等预后或临床变量无关。总之，在相当比例的胰腺癌患者中已显示出针对muRas蛋白的天然T细胞反应，可用于免疫刺激治疗方法。
