Carpentier A F, Rosenfeld M R, Delattre J Y, Whalen R G, Posner J B, Dalmau J
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 1998 Nov;4(11):2819-24.
Some patients with small cell lung cancer (SCLC) or neuroblastoma develop an immune response against HuD, a human homologue of the Drosophila protein, elav, which is expressed in the nucleus and to a lesser degree the cytoplasm of neurons and tumor cells. This immune response is characterized by antibodies (anti-Hu) that at high titers are associated with a disease called paraneoplastic encephalomyelitis/sensory neuronopathy, in which infiltrates of T cells are found in the tumor and nervous system. Although all SCLCs express HuD, anti-Hu antibodies are identified in only 17% of patients with SCLC, usually at low titers, and are associated with indolent tumor growth. To determine whether the anti-Hu immune response causes indolent tumor growth, we developed an animal model using HuD DNA immunization. We found that a plasmid coding for a secreted form of HuD induced a strong and specific anti-Hu response. Immunized animals were challenged by s.c. implantation of a neuroblastoma cell line that constitutively expresses HuD. When compared with controls, mice immunized with the secreted HuD showed significant tumor growth inhibition (51% reduction volume; P = 0.0012), and 14% of them had complete tumor rejection. Tumors from these animals showed three times more CD3+ lymphocytic infiltrates than those from control mice and had a higher CD8+:CD4+ ratio. None of the animals developed neurological deficits or neuropathological evidence of nervous system pathology. In this mouse model of neuroblastoma, DNA immunization with HuD resulted in tumor growth inhibition but did not induce neurological disease. This model closely mimics the clinical course of more indolent tumor growth seen in patients with the anti-Hu immune response.
一些小细胞肺癌（SCLC）或神经母细胞瘤患者会产生针对HuD的免疫反应，HuD是果蝇蛋白elav的人类同源物，在神经元和肿瘤细胞的细胞核中表达，在细胞质中表达程度较低。这种免疫反应的特征是产生抗体（抗Hu），高滴度的抗Hu抗体与一种称为副肿瘤性脑脊髓炎/感觉神经元病的疾病相关，在肿瘤和神经系统中可发现T细胞浸润。尽管所有SCLC都表达HuD，但仅17%的SCLC患者可检测到抗Hu抗体，通常滴度较低，且与肿瘤生长缓慢有关。为了确定抗Hu免疫反应是否导致肿瘤生长缓慢，我们利用HuD DNA免疫建立了一种动物模型。我们发现，编码分泌形式HuD的质粒可诱导强烈且特异性的抗Hu反应。用组成性表达HuD的神经母细胞瘤细胞系皮下接种免疫动物。与对照组相比，用分泌型HuD免疫的小鼠肿瘤生长受到显著抑制（体积减少51%；P = 0.0012），其中14%的小鼠肿瘤完全消退。这些动物的肿瘤中CD3+淋巴细胞浸润比对照小鼠的肿瘤多两倍，且CD8+:CD4+比值更高。所有动物均未出现神经功能缺损或神经系统病理的神经病理学证据。在这个神经母细胞瘤小鼠模型中，用HuD进行DNA免疫导致肿瘤生长抑制，但未诱发神经疾病。该模型紧密模拟了抗Hu免疫反应患者中更缓慢的肿瘤生长临床过程。
