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.
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