CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma
CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma
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DOI：
10.1126/scitranslmed.3001620
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发表时间：
2011-03-16
影响因子：
17.1
通讯作者：
Dornan, David
中科院分区：
文献类型：
--
作者：
Burington, Bart;Yue, Peng;Dornan, David
B细胞是适应性免疫反应的关键组成部分，其主要功能是产生针对外来抗原的抗体，以及进行同型类转换，改变抗体的重链，使其能够与不同的效应细胞相互作用。CD40是肿瘤坏死因子超家族细胞表面受体的一员，将生存信号传递给B细胞。相反，在B细胞癌中，CD40信号的刺激导致非均匀反应，细胞有时会因治疗而死亡，这取决于所研究的系统。在一组非霍奇金淋巴瘤细胞系中，我们发现对CD40刺激的敏感性与肿瘤抑制因子p53突变之间存在关联。与p53的肿瘤抑制作用一致，我们发现更高水平的内在DNA损伤和增加的增殖率，以及更高水平的BCL6（一种转录抑制原癌基因）与对CD40刺激的敏感性有关。此外，CD40治疗耐药细胞系在引入dna损伤剂后对CD40刺激敏感。通过基因表达分析，我们还发现耐药细胞系表现出预先存在的活化CD40途径，并且在细胞系和小鼠异种移植模型中，包含CD40靶基因的mRNA表达特征预测了对CD40活化剂的敏感性和耐药性。最后，基因标记预测弥漫性大B细胞淋巴瘤患者接受dacetuzumab（一种具有部分CD40激动剂活性的单克隆抗体）治疗的肿瘤缩小和无进展生存期。这些数据表明，CD40通路激活状态可能有助于预测CD40刺激治疗药物的抗肿瘤活性。
The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.