TUMOR-SPECIFIC KILLER-CELLS IN PARANEOPLASTIC CEREBELLAR DEGENERATION

Models for immune-mediated tumor regression in mice have defined an es sential role for cytotoxic T lymphocytes (CTLs); however, naturally oc curring tumor immunity in humans is poorly understood(1). Patients wit h paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovar ian cancer. Although tumor immunity and autoimmune neuronal degenerati on in PCD correlates with a specific antibody response to the tumor an d brain antigen cdr2(2,3), this humoral response has not been shown to be pathogenic(3,4). Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA- A2.1(+) PCD patients, providing the first description, to our knowledg e, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby i mmature dendritic cells that engulf apoptotic tumor cells can mature a nd migrate to draining lymph organs where they could induce a CTL resp onse to tissue-restricted antigens. In PCD, peripheral activation of c dr2-specific CTLs is likely to contribute to the subsequent developmen t of the autoimmune neuronal degeneration.