An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model
An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model
复制标题
DOI：
10.1111/j.1365-3083.2007.01927.x
复制
发表时间：
2007-05-01
影响因子：
3.7
通讯作者：
Antonia, S. J.
中科院分区：
文献类型：
--
作者：
Hunter, T. B.;Alsarraj, M.;Antonia, S. J.
CD 40介导的相互作用在对包括癌症在内的多种疾病的应答中起重要作用。通过CD 40 L结合抗原呈递细胞（即树突状细胞（DC））上的CD 40导致共刺激分子B7.1和B7.2（CD 80和CD 86）的成熟和上调。这些分子对于随后的T细胞的抗原特异性活化是必需的。T细胞活化是特异性抗肿瘤免疫应答的一个关键方面，已成为各种癌症免疫治疗方法的焦点。涉及免疫干预的临床试验已经显示出临床反应，证实免疫系统可以用于治疗癌症。然而，临床反应率一直很低，这意味着需要新的免疫策略。为此，已经开发了特异于CD 40的激动剂抗体CP-870，893。利用完全自体混合的结节细胞/淋巴结细胞模型来证明CP-870，893促进淋巴结来源的T细胞对自体结节的反应性。具体而言，来自肿瘤引流淋巴结的T细胞对自体turnout细胞无反应;然而，在CP-870，893存在下，这种无反应性被逆转，如淋巴结细胞增殖和细胞因子分泌所示。用CP-870，893处理的单核细胞衍生的DC一致地显示成熟表型：在用抗体处理之后，上调CD 80、CD 83、CD 86和HLA-DR表达，增加Mip 1 α和IL-12分泌，并且丧失外源性抗原呈递能力。这些数据表明CP-870，893结合并激活DC，最终驱动特异性抗肿瘤T细胞应答。
CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells, namely dendritic cells (DC), by CD40L leads to maturation and up-regulation of co-stimulatory molecules B7.1 and B7.2 (CD80 and CD86). These molecules are requisite to subsequent antigen-specific activation of T cells. T-cell activation is a critical aspect of specific anti-tumour immune responses that have become the focus of a variety of cancer immunotherapy approaches. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40, CP-870,893, has been developed. A fully autologous mixed turnout cell/lymph node cell model was utilized to demonstrate that CP-870,893 Promotes the responsiveness of lymph node-derived T cells to autologous turnout. Specifically, T cells from the tumour-draining lymph nodes are not responsive to autologous turnout cells; however, in the presence of CP-870,893, this unresponsiveness is reversed, as indicated by lymph node cell proliferation and cytokine secretion. Monocyte-derived DC treated with CP-870,893 consistently display a mature phenotype: up-regulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 alpha and IL-12 secretion, and the loss of exogenous antigen-presenting capability subsequent to treatment with the antibody. These data indicate that CP-870,893 binds to and activates DC, ultimately driving a specific anti-tumour T-cell response.