Promoting Tumor Immunity by Cross-Linking B7-DC

主动免疫疗法的主要目标是动员针对癌症的免疫应答。的能力 识别和破坏肿瘤细胞的宿主免疫性已经很好地建立。但是，尝试激活主机 抗肿瘤免疫应答仅部分成功。CD 8 + T细胞经常扩增， 甚至渗透到肿瘤床，但肿瘤逃避机制阻止了它们摧毁生长中的癌症的能力。一 一种新的免疫调节抗体，称为B7-DC XAb，已从Waldenstrom病患者中分离出来 巨球蛋白血症。这种抗体激活小鼠和人类树突状细胞的方式不同于 其他已知的免疫激活剂，快速增强T细胞细胞毒性应答， 肿瘤细胞用免疫调节剂治疗动物，可防止黑色素瘤、肾细胞 癌，淋巴瘤，白血病和乳腺癌，证明了该试剂的潜在应用， 治疗各种癌症值得注意的是，当B7-DC XAb与 使用其他无效的疫苗，动物容易发生自发性和侵袭性乳腺癌， 肿瘤保持无癌。使用小鼠模型的实验提出（1）定义本质 这种有效治疗乳腺癌的成分，（2）确定肿瘤的机制 破坏，（3）表征靶抗原和识别它们的T细胞的起源，和（4） 阐明树突状细胞活化、T细胞活化和调节 调节性T细胞网络均与B7-DC XAb免疫诱导的肿瘤免疫相关 调制器这些研究与开发针对免疫缺陷病毒的免疫治疗策略高度相关。 治疗人类癌症，因为正在研究的免疫增强剂是一种结合 并通过激活与最初定义的那些类似的信号通路来刺激人类树突细胞。 老鼠.此外，通过B7-DC XAb处理活化的人树突状细胞显示类似的功能， 在小鼠中观察到的特性，包括增强的抗原摄取，细胞因子释放的模式， 和增强的激活肿瘤特异性细胞毒性T细胞的能力。

A principal goal of active immunotherapy is to mobilize the immune response against cancer. The ability of host immunity to recognize and destroy tumor cells is well established. However, attempts to activate host anti-tumor immune responses have been only partially successful. Frequently CD8+ T cells are expanded and even infiltrate tumor beds, but tumor evasion mechanisms block their ability to destroy growing cancers. A new immune modulatory antibody, called B7-DC XAb, has been isolated from a patient with Waldenstrom¿s macroglobulinemia. This antibody activates both mouse and human dendritic cells in a manner distinct from other known immune activators, rapidly potentiating T cell cytotoxic responses that can recognize and kill tumor cells. Treatment of animals with the immune modulator prevented the outgrowth of melanoma, renal cell carcinoma, lymphoma, leukemia, and breast cancer, demonstrating the potential application of this reagent to the treatment of a wide variety of cancers. Remarkably, when B7-DC XAb was given to animals in conjunction with an otherwise ineffective vaccine, animals prone to the development of spontaneous and aggressive breast tumors remained cancer free. Experiments using mouse models are proposed (1) to define the essential components of this effective treatment against breast cancer, (2) to determine the mechanism of tumor destruction, (3) to characterize the targeted antigens and the origin of the T cells that recognize them, and (4) to elucidate the molecular mechanisms underlying dendritic cell activation, T cell activation, and modulation of the T regulatory cell network that are all associated with tumor immunity induced by the B7-DC XAb immune modulator. These studies are highly relevant to the development of an immunotherapy strategy for the treatment of human cancers because the immune potentiator being studied is a human antibody that binds to and stimulates human dendritic cells by activating similar signaling pathways to those originally defined in the mouse. Furthermore, human dendritic cells activated by B7-DC XAb-treatment display similar functional properties to those seen in the mouse, including enhanced antigen uptake, the patterns in cytokine release, and an enhanced ability to activate tumor specific cytotoxic T cells.