HYBRIDOMAS REVEAL SHARED IMMUNODOMINANT EPITOPES OF GAMMA-GLUTAMYL-TRANSFERASE ISOFORMS FROM HUMAN KIDNEY AND RENAL-CELL CARCINOMA

Metastatic renal cell carcinoma (RCC) is a tumor with a poor prognosis resistant to chemotherapy and irradiation. However, in rare cases, sp ontaneous regressions of metastases after nephrectomy have been report ed that were ascribed to destruction of the tumor by the immune system . In earlier studies, we and others identified the expression of modif ied antigens in RCC. In particular, a concanavalin A-binding isoform o f gamma-glutamyltransferase (gamma GT) comprises about 50% of the enzy matic activity found in the tumor tissue of many RCC patients. The mon oclonal antibody 138H11, directed against all human gamma GT isoforms, revealed a membranous expression of gamma GT around RCC cells compare d to the restricted, apical pattern of renal cells. These data raised the question why the RCC-specific gamma GT, exposed to the immune syst em in vivo, is not immunogenic in patients with RCC. To address this q uestion, we generated mouse hybridomas against highly purified human R CC gamma GT. Although we obtained a large panel of hybridomas that pro duced antibodies reacting immunohistochemically in a gamma GT-specific manner, all antibodies stained normal kidney gamma GT as well as RCC gamma GT. These results suggest that the biochemical features specific for RCC gamma GT are not necessarily reflected by specific antigenic determinants that could be differentiated by the immune system of the challenged mice. The lack of immunogenic epitopes different from norma l gamma GT enzyme may offer an explanation why IGT produced by RCC can escape immunological surveillance. Metastatic renal cell carcinoma (R CC) is a tumor with a poor prognosis resistant to chemotherapy and irr adiation. However, in rare cases, spontaneous regressions of metastase s after nephrectomy have been reported that were ascribed to destructi on of the tumor by the immune system. In earlier studies, we and other s identified the expression of modified antigens in RCC. In particular , a concanavalin A-binding isoform of gamma-glutamyltransferase (gamma GT) comprises about 50% of the enzymatic activity found in the tumor tissue of many RCC patients. The monoclonal antibody 138H11, directed against all human gamma GT isoforms, revealed a membranous expression of gamma GT around RCC cells compared to the restricted, apical patter n of renal cells. These data raised the question why the RCC-specific gamma GT, exposed to the immune system in vivo, is not immunogenic in patients with RCC. To address this question, we generated mouse hybrid omas against highly purified human RCC gamma GT. Although we obtained a large panel of hybridomas that produced antibodies reacting immunohi stochemically in a gamma GT-specific manner, all antibodies stained no rmal kidney gamma GT as well as RCC gamma GT. These results suggest th at the biochemical features specific for RCC gamma GT are not necessar ily reflected by specific antigenic determinants that could be differe ntiated by the immune system of the challenged mice. The lack of immun ogenic epitopes different from normal gamma GT enzyme may offer an exp lanation why IGT produced by RCC can escape immunological surveillance .