CD70 (TNFSF7) is expressed at high prevalence in renal cell carcinomas and is rapidly internalised on antibody binding

Abstract

In order to identify potential markers of renal cancer, the plasma membrane protein content of renal cell carcinoma (RCC)-derived cell lines was annotated using a proteomics process. One unusual protein identified at high levels in A498 and 786-O cells was CD70 (TNFSF7), a type II transmembrane receptor normally expressed on a subset of B, T and NK cells, where it plays a costimulatory role in immune cell activation. Immunohistochemical analysis of CD70 expression in multiple carcinoma types demonstrated strong CD70 staining in RCC tissues. Metastatic tissues from eight of 11 patients with clear cell RCC were positive for CD70 expression. Immunocytochemical analysis demonstrated that binding of an anti-CD70 antibody to CD70 endogenously expressed on the surface of A498 and 786-O cell lines resulted in the rapid internalisation of the antibody -receptor complex. Coincubation of the internalising anti-CD70 antibody with a saporin-conjugated secondary antibody before addition to A498 cells resulted in 50% cell killing. These data indicate that CD70 represents a potential target antigen for toxin-conjugated therapeutic antibody treatment of RCC.

pVHL/HIF-Regulated CD70 Expression Is Associated with Infiltration of CD27+ Lymphocytes and Increased Serum Levels of Soluble CD27 in Clear Cell Renal Cell Carcinoma

“…IHC TMA staining of more than 600 RCCs showed abnormal CD70 expression in 78% of ccRCCs, which was consistent with previously described frequencies (11,12). Our comprehensive CD70 analysis of 348 papillary RCCs revealed 11% strongly and 22% moderately expressing tumors, which was lower compared with the frequencies observed in recently published smaller cohorts (10,12,13).…”

“…Altered CD70 expression was found in hematologic malignancies and also in solid tumors, such as nasopharyngeal carcinoma, thymic carcinoma, and brain tumors (9). The most frequent expression was reported in RCC (10)(11)(12)(13), but the mechanism that leads to the upregulation of CD70 in this tumor type is still unclear. Interestingly, CD70 expression is less prevalent in VHL unrelated RCC subtypes.…”

Generation of a Mouse Model of Von Hippel–Lindau Kidney Disease Leading to Renal Cancers by Expression of a Constitutively Active Mutant of HIF1α

“…We also observe some molecular abnormalities usually seen in tumor cells, such as increased cell proliferation and DNA DSBs. Furthermore, we observe abnormalities characteristic of ccRCC, such as renal cysts, disorganized “clear” cell PTs, and CD70 overexpression (34). We observed no abnormalities in other organs of the γ-HIF1α-M3 TG + lines, most likely because the GGT promoter drives transgene expression only in kidney PT cells, thought to be the cells of origin of human ccRCC (40).…”

Investigational antibody drug conjugates for solid tumors

“…Although CD70, the ligand for the co-stimulatory receptor CD27 and member of the TNF superfamily, is expressed to some degree by subpopulations of highly activated hematopoietic cells, namely activated T and B lymphocytes and mature dendritic cells, it is robustly overexpressed by many cancers and is, therefore, considered an ideal target for ADC development [16,25,26,30,59]. The anti-CD70 immunoconjugate MDX-1203, developed by Medarex/ BMS (New York, NY, USA) using their UltiMAb transgenic mouse platform, comprises a human mAb directed against the extracellular domain of the CD70 molecule.…”

“…CD70 is upregulated on several carcinomas, including renal cell carcinoma (RCC) [16,[25][26][27], thymic carcinoma [28], nasopharyngeal [29], glioblastoma and astrocytomas [30]. On normal cells, CD70 expression is limited to activated T-cells and B-cells and is undetectable on normal lymphocytes and parenchymal cells [31] and, therefore, it is considered an ideal target for cancer immunotherapy [10].…”