Hybridomas Reveal Shared Immunodominant Epitopes of γ-Glutamyltransferase Isoforms from Human Kidney and Renal Cell Carcinoma

Abstract

Metastatic renal cell carcinoma (RCC) is a tumor with a poor prognosis resistant to chemotherapy and irradiation. However, in rare cases, spontaneous regressions of metastases after nephrectomy have been reported that were ascribed to destruction of the tumor by the immune system. In earlier studies, we and others identified the expression of modified antigens in RCC. In particular, a concanavalin A-binding isoform of γ-glutamyltrans-ferase (γGT) comprises about 50% of the enzymatic activity found in the tumor tissue of many RCC patients. The monoclonal antibody 138H11, directed against all human γGT isoforms, revealed a membranous expression of γGT around RCC cells compared to the restricted, apical pattern of renal cells. These data raised the question why the RCC-specific γGT, exposed to the immune system in vivo, is not immunogenic in patients with RCC. To address this question, we generated mouse hybridomas against highly purified human RCC γGT. Although we obtained a large panel of hybridomas that produced antibodies reacting immunohisto-chemically in a γGT-specific manner, all antibodies stained normal kidney γGT as well as RCC γGT. These results suggest that the biochemical features specific for RCC γGT are not necessarily reflected by specific anti-genic determinants that could be differentiated by the immune system of the challenged mice. The lack of immunogenic epitopes different from normal γGT enzyme may offer an explanation why γGT produced by RCC can escape immunological surveillance.

Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma

“…These surfaces are usually not connected to the circulation. In contrast, GGT is expressed over the entire cell surface in RCC ( Fischer and Scherberich, 1996 ; Kaufmann et al , 1997 ) and is therefore accessible through the circulation. This may subsequently lead to elevated serum levels of GGT and higher intracellular levels of GSH ( Lusini et al , 2001 ), which correlate with the tumour burden.…”

Immunohistochemical differentiation of metastases of renal carcinomas versus other carcinomas with anti‐γGT monoclonal antibody 138H11

“…8) and would therefore not be accessible to mAb 138H11 in circulation. This was demonstrated earlier in an extracorporeal perfusion model with human tumourbearing kidneys when 99m Tc-labelled mAb 138H11 was up to 20-fold enriched in the tumour compared to normal tissue [16][17][18] .…”

Preoperative Gamma-Glutamyltransferase Is Associated with Cancer-Specific Survival and Recurrence-Free Survival of Nonmetastatic Renal Cell Carcinoma with Venous Tumor Thrombus

“…Accumulating evidence has suggested that GGT is deregulated in cancer cells and could reflect tumor progression and aggressiveness [ 20 ]. Although GGT is limited to the brush border membrane of proximal tubules of the normal kidney tissues, it has been confirmed that GGT is expressed extensively on the membrane of RCC cells [ 21 , 22 ]. As a membrane-bound enzyme, GGT plays a substantial role in sustaining the production of intracellular glutathione (GSH), which can function as an important antioxidant to protect cells from reactive oxygen compounds and free radicals.…”