Study of the paraneoplastic neurologic disorders (PNDs) offers a unique opportunity to study cellular mechanisms of naturally occurring tumor immunity in humans. Patients with these neurologic disorders harbor systemic tumors that express proteins whose normal expression is entirely restricted to neurons. Perhaps in part because such proteins are normally concealed in immune privileged sites, their ectopic expression in tumors is believed to result in a potent tumor immune response that is associated with clinically evident tumor suppression. These patients come to clinical attention, however, when their immune response begins, by unknown mechanisms, to recognize and destroy not only the tumor cells, but also neurons that normally express the same antigen. Among patients with a specific PND, paraneoplastic cerebellar degeneration (PCD), which develops in women with evidence of tumor immunity to occult breast or ovarian cancers, cerebellar Purkinje neurons are destroyed. PCD patients harbor serum and CSF antibodies specific to a protein termed cdr2. Both PCD tumors and Purkinje neurons express cdr2. We have also found that the cdr2 antigen is expressed in a wider range of gynecologic tumors than the rare co-incidence of tumor immunity and cerebellar degeneration present in PCD might suggest. In preliminary studies of tumors obtained from neurologically normal tumor patients, we have found cdr2 antigen expression in 60% of ovarian tumors and 25% of breast tumors. In preliminary experiments we have found consistent evidence that PCD patients harbor cytotoxic T-cell lymphocytes (CTLs) able to kill cells presenting cdr2 peptide. We detected these CTLs using a simple recall assay and autologous dendritic cells (DCs) to activate their T cells.
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