Analysis of mechanism of intravesical BCG therapy for bladder cancer

卡介苗（BCG）膀胱灌注治疗被认为是目前治疗膀胱癌最成功的免疫疗法，但其确切的抗肿瘤机制尚不清楚。BCG敏感的树突状细胞（DC）被认为是诱导肿瘤特异性免疫的关键细胞。然而，由于这些DC通常不是肿瘤细胞，因此它们可以通过II类MHC分子呈递从外部肿瘤获得的抗原分子，由此不会产生肿瘤特异性I类MHC分子限制的CD 8阳性细胞毒性T淋巴细胞（CTL）。然而，最近的研究结果表明，表达DEC-205的DC亚群可以通过“交叉呈递”呈递与其I类MHC相关的捕获的抗原分子。在这项研究中，我们发现，我们可以选择性地激活DEC-205表达的树突状细胞时，他们与活BCG刺激。由于这种活的BCG似乎对DC有毒，我们目前已经检查了BCG的无毒组分，如云母酸或脂阿拉伯甘露聚糖（LAM），并发现这些BCG衍生的组分具有刺激DEC-205阳性DC的效力。在此基础上，我们试图为人类膀胱癌提供一种新的更安全的免疫治疗方法。

Intravesical bacillus Calmette-Guerin (BCG) therapy is considered the most successful immunotherapy against solid tumor of human bladder carcinoma, but the precise anti-tumor mechanism is still unknown. BCG-susceptible dendritic cells (DCs) have been thought as key cells to induce tumor-specific immunity. However, because these DCs will not be tumorcells generally and thus, they can present antigenic molecule obtained from external tumors via class II MHC molecules, by which tumor-specific class-I MHC molecule-restricted CD8-positive cytotoxoc T lymphocytes (CTLs) will not be generated. Nevertheless, recent findings demonstrated that DC-subpopulation expressing DEC-205 can present captured antigenic molecules associated with their class I MHC by “cross-presentation”. In this study, we found that we could selectively activate DEC-205-expressing DCs when they were stimulated with viable BCG. Because such viable BCG seems to be toxic to DCs, we have currently examined the non-toxic components of BCG such as micolic acid or lipoaravinomannan (LAM) and found that these BCG-derived components have a potency to stimulate DEC-205-positive DCs. Based on the observation, we are trying to provide a new safer immunotherapy for human bladder carcinoma.