AN ANIMAL MODEL OF NATURALLY OCCURRING TUMOR IMMUNITY

副肿瘤性小脑变性（PCD）提供了一个重要的和独特的例子，自然发生的乳腺肿瘤免疫在人类。 PCD的特征在于针对通常在小脑中表达的称为cdr2的肿瘤抗原的高滴度抗体。 PCD患者对其肿瘤产生有效的免疫反应，然后引起临床关注，伴有严重的神经功能障碍。 有人提出，当cdr2被识别为乳腺或卵巢肿瘤中的外来抗原时，免疫系统启动PCD。 我们假设PCD中发生的肿瘤免疫和神经元破坏不是针对cdr 2的抗体的结果，而是由杀死表达cdr 2的细胞的细胞毒性T细胞（CTL）引起的。 这一假设部分是基于研究人员未能通过诱导cdr 2抗体来创建PCD动物模型，部分是基于我们发现能够杀死PCD患者中的肿瘤的cdr 2特异性CTL。 我们建议通过产生PCD的动物模型来检验这一假设并加深我们对乳腺肿瘤免疫的理解。由于我们也发现cdr2在从神经系统正常个体获得的乳腺肿瘤中表达，我们的研究为人类乳腺癌免疫提供了一种新的重要方法。

Paraneoplastic cerebellar degeneration (PCD) provides an important and unique example of naturally occurring breast tumor immunity in humans. PCD is characterized by a high titer antibody directed against a tumor antigen termed cdr2 that is normally expressed in the cerebellum. PCD patients develop an effective immune response to their tumors, and then come to clinical attention with severe neurologic dysfunction. It is proposed that the immune system initiates PCD when cdr2 is recognized as a foreign antigen in breast or ovarian tumors. We have hypothesized that the tumor immunity and neuronal destruction that occurs in PCD is not a result of antibodies against cdr2, but instead results from cytotoxic T cells (CTLs) that kill cdr2 expressing cells. This hypothesis is based in part on the failure of investigators to create an animal model of PCD by inducing cdr2 antibodies, and in part on our finding of cdr2-specific CTLs capable of killing tumors in PCD patients. We propose to test this hypothesis and deepen our understanding of breast tumor immunity by generating an animal model of PCD. Since we also find cdr2 expression in breast tumors obtained from neurologically normal individuals, our studies provide a new and important approach to breast cancer immunity in humans.