Brandau S, Riemensberger J, Jacobsen M, Kemp D, Zhao W, Zhao X, Jocham D, Ratliff T L, Böhle A
Division of Immunotherapy, Research Center Borstel, Borstel, Germany.
Int J Cancer. 2001 Jun 1;92(5):697-702. doi: 10.1002/1097-0215(20010601)92:5<697::aid-ijc1245>3.0.co;2-z.
Adjuvant intravesical bacillus Calmette-Guérin (BCG) therapy is a well-established and successful adjuvant immunotherapy in the treatment of superficial bladder cancer. Although the function of natural killer (NK) cells in other immunotherapeutic regimens (e.g., lymphokine-activated killer [LAK] cell or interleukin-2 [IL-2] therapy) has been established, the contribution of NK cells to effective BCG immunotherapy is not clear. We used a human in vitro system to analyze the role of NK cells in BCG-induced cellular cytotoxicity. After stimulation of mononuclear cells with BCG for 7 days, these BCG-activated killer (BAK) cells displayed substantial cytotoxicity against bladder tumor cells. Magnetic depletion experiments and fluorescence activated cell sorting revealed that NK cells were the major effector cell population. To address NK cell function in vivo, we studied a syngeneic orthotopic murine bladder cancer model and compared BCG immunotherapy in C57BL/6 wild-type mice, NK-deficient beige mice and mice treated with anti-NK1.1 monoclonal antibody. Four weekly instillations of viable BCG significantly prolonged survival in wild-type mice compared with control mice treated with solvent alone. In contrast, BCG therapy was completely ineffective in NK-deficient beige mice and in mice treated with anti-NK1.1 monoclonal antibody. These findings suggest a key role for NK cells during BCG immunotherapy.
辅助性膀胱内卡介苗（BCG）治疗是治疗浅表性膀胱癌一种成熟且成功的辅助免疫疗法。虽然自然杀伤（NK）细胞在其他免疫治疗方案（如淋巴因子激活的杀伤细胞[LAK]或白细胞介素-2[IL-2]治疗）中的作用已得到证实，但NK细胞对有效的BCG免疫治疗的贡献尚不清楚。我们使用一种体外人体系统来分析NK细胞在BCG诱导的细胞毒性中的作用。用BCG刺激单核细胞7天后，这些BCG激活的杀伤（BAK）细胞对膀胱肿瘤细胞表现出显著的细胞毒性。磁性去除实验和荧光激活细胞分选显示NK细胞是主要的效应细胞群体。为了研究NK细胞在体内的功能，我们研究了一种同基因原位小鼠膀胱癌模型，并比较了C57BL/6野生型小鼠、NK缺陷的米色小鼠和用抗NK1.1单克隆抗体治疗的小鼠的BCG免疫治疗效果。与仅用溶剂治疗的对照小鼠相比，每周4次灌注活BCG显著延长了野生型小鼠的生存期。相比之下，BCG治疗在NK缺陷的米色小鼠和用抗NK1.1单克隆抗体治疗的小鼠中完全无效。这些发现表明NK细胞在BCG免疫治疗中起关键作用。
