The renal cell carcinoma-associated antigen G250 encodes a human leukocyte antigen (HLA)-A2.1-restricted epitope recognized by cytotoxic T lymphocytes.
Evidence has accumulated that the immune system can play a significant role in the defense against tumors in humans. Especially melanoma and renal cell carcinoma (RCC) are considered immunogenic tumors. In contrast to melanoma, hardly any RCC-associated antigens have been identified as targets for RCC-reactive T cells. Here, we report the identification of a human leukocyte antigen (HLA)-A2.1-restricted T-cell epitope within the G250 antigen. This antigen is expressed in 85% of RCCs but not by neighboring normal kidney tissue and has recently been molecularly defined and shown to be identical to MN/CA IX. Computer-aided motif prediction revealed the presence of 60 potential HLA-A2.1-binding peptides within the G250 antigen. Subsequent binding analysis showed that 13 of these peptides bound to HLA-A2.1 with high-to-intermediate affinity. Analysis of their immunogenicity in HLA-A2.1Kb transgenic mice indicated that 4 of the 13 peptides gave rise to cytotoxic T lymphocytes (CTLs) capable of lysing peptide-loaded target cells. However, only the G250 peptide 254-262 induced CTLs that recognized target cells that endogenously expressed the G250 antigen. Similarly, we were also able to raise human CTLs against the G250 peptide 254-262, which lysed target cells that endogenously expressed the G250 antigen. These findings and the high prevalence of this antigen in RCC patients makes G250 a potential target for anti-RCC immunotherapy.
Vissers
J L
JL
Tumor Immunology Laboratory, University Hospital Nijmegen St. Radboud, The Netherlands.
De Vries
I J
IJ
Schreurs
M W
MW
Engelen
L P
LP
Oosterwijk
E
E
Figdor
C G
CG
Adema
G J
GJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000939:Epitopes; C106533:G250 monoclonal antibody; D015789:HLA-A2 Antigen; D010455:Peptides; C400566:antigen G250