Schlienger Katia, Chu Christina S, Woo Edward Y, Rivers Patricia M, Toll Alanna J, Hudson Brian, Maus Marcela V, Riley James L, Choi Yongwon, Coukos George, Kaiser Larry R, Rubin Stephen C, Levine Bruce L, Carroll Richard G, June Carl H
Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Clin Cancer Res. 2003 Apr;9(4):1517-27.
The use of mature dendritic cells (DCs) presenting tumor-associated antigens (TAAs) to trigger tumor-specific T cells in vivo or in vitro represents a promising approach for cancer immunotherapy. We hypothesized that tumor antigens, mostly unidentified, are present on ovarian tumor cells and that mature DCs could be used to generate tumor-specific responses in unprimed patients. We also sought to measure preexisting antitumor immunity in patients with advanced ovarian cancer.
Autologous DCs from 10 patients with ovarian cancer were pulsed with killed autologous primary tumors as a source of TAAs. DCs were then cultured in the presence of tumor necrosis factor alpha + TRANCE (tumor necrosis factor-related activation-induced cytokine) to induce maturation. Mature TAA-pulsed DCs were used in vitro to stimulate tumor-specific peripheral blood T cells.
TRANCE and CD40 ligand were effective at maturing DCs. T-cell lines were generated in vitro that were capable of secreting IFN-gamma in response to autologous tumor. These tumor-specific T cells were MHC class I restricted. The frequency of tumor-specific T cells in uncultured cells from malignant ascites fluid and peripheral blood was measured in the same patients.
IFN-gamma-secreting tumor-specific T cells were demonstrated at baseline in uncultured T cells from some unvaccinated ovarian cancer patients; however, the T cells could not kill autologous tumor. These data demonstrate that mature DCs presenting tumor antigens from engulfed autologous tumors can be used to augment antitumor immunity in vitro in patients with epithelial ovarian cancer. The results support the feasibility of therapeutic vaccination of ovarian cancer patients.
利用呈递肿瘤相关抗原（TAA）的成熟树突状细胞（DC）在体内或体外触发肿瘤特异性T细胞，是癌症免疫治疗的一种有前景的方法。我们假设，卵巢肿瘤细胞上存在大多尚未明确的肿瘤抗原，并且成熟DC可用于在未致敏患者中产生肿瘤特异性反应。我们还试图测量晚期卵巢癌患者预先存在的抗肿瘤免疫力。
从10例卵巢癌患者中获取自体DC，用灭活的自体原发性肿瘤作为TAA来源进行脉冲处理。然后在肿瘤坏死因子α + TRANCE（肿瘤坏死因子相关激活诱导细胞因子）存在的情况下培养DC以诱导成熟。成熟的TAA脉冲DC用于体外刺激肿瘤特异性外周血T细胞。
TRANCE和CD40配体在使DC成熟方面有效。体外产生了能够响应自体肿瘤分泌干扰素γ的T细胞系。这些肿瘤特异性T细胞受MHC I类限制。在同一患者中测量了来自恶性腹水和外周血的未培养细胞中肿瘤特异性T细胞的频率。
在一些未接种疫苗的卵巢癌患者未培养的T细胞中，在基线时证明了分泌干扰素γ的肿瘤特异性T细胞；然而，这些T细胞不能杀伤自体肿瘤。这些数据表明，呈递来自吞噬的自体肿瘤的肿瘤抗原的成熟DC可用于增强上皮性卵巢癌患者的体外抗肿瘤免疫力。结果支持卵巢癌患者治疗性疫苗接种的可行性。
