THE LONG-TERM OBJECTIVE OF THIS PROJECT IS TO UNDERSTAND THEMOLECULAR BASIS OF T CELL RECOGNITION OF TUMOR ANTIGENS OF LUNG CARCINOMA.

THE LONG-TERM OBJECTIVE OF THIS PROJECT IS TO UNDERSTAND THEMOLECULAR BASIS OF T CELL RECOGNITION OF TUMOR ANTIGENS OF LUNG CARCINOMA. THE SPECIFIC AIMS OF THE PROPOSED STUDY ARE(1) TO CHARACTERIZE THE GENES ENCODING T CELL ANTIGEN RECEPTORS (TCAR) FROM THE TUMOR INFILTRATING LYMPHOCYTES; AND (2) TO INVESTIGATE WHETHER THERE IS A LIMITED EXPRESSIONOF T CELL CLONOTYPES DIRECTED AGAINST TUMOR CELLS AT THE SITE OF LUNG TUMORS. A T CELL CLONOTYPE IS DEFINED BY TCAR,WHICH IS COMPOSED OF AN ALPHA AND A BETA POLYPEPTIDE CHAIN. EACH ALPHA AND BETA CHAIN CONSISTS OF VARIABLE (V) AND DIVERSITY (D), JOINING (J) AND CONSTANT (C) DOMAINS. ESTIMATED TOTAL NUMBERS OF V-BETA GENES OF THE TCAR IN THE MURINE SYSTEM ARE APPROXIMATELY TWENTY. PHASE I EFFORTS WILL INCLUDE (1) AN ANALYSIS OF THE TOTAL V-BETA GENE REPERTOIRE AVAILABLE IN HUMANS AND (2) AN ANALYSIS OF THOSE V-BETA GENES EXPRESSED IN THE TUMOR DERIVED T CELLS. FOR THESE STUDIES, A CDNA LIBRARY WILL BE PREPARED FROM TUMOR- DERIVED T CELLS USING A 5' BETA CONSTANT REGION SEQUENCE AS A PRIMER AND APPROPRIATE PHAGES AS VECTOR. COMPARATIVE ANALYSIS OF THESE TUMOR-DERIVED V-BETA DNA SEQUENCES WITH THE COMPLETE REPERTOIRE OF V-BETA SEUENCES OBTAINED FROM A LARGE PERIPHERAL T CELL LIBRARY WILL BE DONE. THESE DNA SEQUENCE ANALYSES MABE EXTENDED TO THE V-ALPHA GENES AND TO THE D AND J REGIONS OF ALPHA AND BETA GENES. THE MOLECULAR ANALYSIS OF THE TUMOR-DERIVED T CELLS MAY PROVIDE A RATIONAL BASIS FOR DEVELOPING T CELL RECEPTOR-ORIENTED DNA PROBES AND MONOCLONAL ANTIBODIES FOR DIAGNOSING AND MONITORING LUNG CANCER PATIENTS.