Breast Tumor Immunity in the Paraneoplastic Neurologic Disorders

摘要

The promise of recent success demonstrating the immunologic recognition of tumor cells has been limited by the paucity of native human tumor specific antigens that might serve as targets for attack. This work focused on a human disorders, paraneoplastic neurologic degeneration (PND), in which breast tumors express tumor specific antigens--proteins normally made only in the nervous system--and come under immunologic attack. In the first Aim we characterized the expression of PND genes in normal tissue and tumor. We found that cdr2, Nova-1 and Nova-2 are all highly restricted in normal tissues, but are expressed in breast and other tumors. This specificity underlies the antigenicity of these proteins in tumor cells, and provides a potential focus for tumor therapy. In Aims II-III we set out to generate animal models of breast tumor immunity against the cdr2 antigen. In parallel, we recently examined tumor immunity in human PND patients, based on our identification of cdr2 as the tumor antigen in these tumors (Aim 1). These studies allowed us to identify cdr2- specific killer T cells in breast cancer patients, and helped guide our approach to animal models. We have now generated cdr2-specific CTLs in mice inoculated with genetically defined transfected tumor cell lines. These studies allow us to overcome unanticipated difficulties originally encountered in these experiments.