Akazawa Takashi, Masuda Hisayo, Saeki Yoshiko, Matsumoto Misako, Takeda Kiyoshi, Tsujimura Kunio, Kuzushima Kiyotaka, Takahashi Toshitada, Azuma Ichiro, Akira Shizuo, Toyoshima Kumao, Seya Tsukasa
Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Cancer Res. 2004 Jan 15;64(2):757-64. doi: 10.1158/0008-5472.can-03-1518.
The Mycobacterium bovis bacillus Calmette-Guérin cell-wall skeleton (BCG-CWS) activates Toll-like receptor (TLR) 2 and TLR4, but unlike the typical TLR4 agonist bacterial lipopolysaccharide barely induces type 1 IFN. BCG-CWS has been used for adjuvant immunotherapy for patients with cancer. We investigated the adjuvant potential of BCG-CWS for induction of CTLs subsequent to TLR-mediated dendritic cell (DC) maturation, using a syngeneic mouse tumor model (B16 melanoma in C57BL/6). We evaluated the retardation of tumor growth and cytotoxic response in wild-type and MyD88-/- mice immunized with tumor debris and/or BCG-CWS. Delays in tumor growth and cytotoxic response were induced by immunization with a mixture of BCG-CWS emulsion and the tumor. BCG-CWS was capable of activating DCs ex vivo by the criteria of CD80/CD86 up-regulation and cytokine (interleukin-12, tumor necrosis factor-alpha) induction. Efficient tumor suppression and ex vivo cytokine induction did not occur in MyD88-deficient mice and cells, suggesting that the MyD88 adapter is crucial for induction of tumor cytotoxicity. Because TLR4 is involved in both MyD88-dependent and -independent pathways and the latter affects DC maturation, our findings indicate that both pathways cooperate to induce CTL-based tumor immunity.
牛分枝杆菌卡介苗细胞壁骨架（BCG-CWS）可激活Toll样受体（TLR）2和TLR4，但与典型的TLR4激动剂细菌脂多糖不同，它几乎不诱导1型干扰素。BCG-CWS已用于癌症患者的辅助免疫治疗。我们使用同基因小鼠肿瘤模型（C57BL/6小鼠的B16黑色素瘤）研究了BCG-CWS在TLR介导的树突状细胞（DC）成熟后诱导细胞毒性T淋巴细胞（CTL）的佐剂潜力。我们评估了用肿瘤碎片和/或BCG-CWS免疫的野生型和MyD88基因敲除小鼠的肿瘤生长延迟和细胞毒性反应。用BCG-CWS乳剂和肿瘤的混合物免疫可诱导肿瘤生长延迟和细胞毒性反应。根据CD80/CD86上调和细胞因子（白细胞介素-12、肿瘤坏死因子-α）诱导的标准，BCG-CWS能够在体外激活DC。在MyD88缺陷的小鼠和细胞中未出现有效的肿瘤抑制和体外细胞因子诱导，这表明MyD88衔接蛋白对于诱导肿瘤细胞毒性至关重要。由于TLR4参与MyD88依赖性和非依赖性途径，且后者影响DC成熟，我们的研究结果表明这两条途径协同作用以诱导基于CTL的肿瘤免疫。
