Ring finger protein 43 as a new target for cancer immunotherapy.
We have performed genome-wide exploration by using cDNA microarray profiling, and successfully identified a new tumor-associated antigen (TAA) that can induce potent cytotoxic T lymphocytes (CTLs) specific to tumor cells. In our preceding study, we identified multiple new genes by using gene expression profiling with a genome-wide cDNA microarray containing 23,040 genes. Among them, we selected RNF43 (ring finger protein 43) as a promising candidate for a TAA expressed by colon cancer cells. In this study, we examined whether the RNF43 protein contains antigenic epitope peptides restricted to HLA-A*0201 or HLA-A*2402. The CTL clones were successfully induced with stimulation by using the peptides binding to HLA-A*0201 (ALWPWLLMA and ALWPWLLMAT) and HLA-A*2402 (NSQPVWLCL), and these CTL clones showed the cytotoxic activity specific to not only the peptide-pulsed targets but also the tumor cells expressing RNF43 and respective HLAs. Lytic activities mediated by two HLA-A2-restricted epitopes were marginal, whereas tumor lysis mediated by the HLA-A24 epitope was clearly better. These findings might be caused by the poor natural presentation of RNF43-11(IX) and RNF43-11(X) by tumors or poor T-cell receptor avidity for these specific epitopes. These results strongly suggest that RNF43 is a new TAA of colon cancer. Furthermore, these results also suggest that our strategy might be a promising one to efficiently discover clinically useful TAAs.
Uchida
Naotaka
N
Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tsunoda
Takuya
T
Wada
Satoshi
S
Furukawa
Yoichi
Y
Nakamura
Yusuke
Y
Tahara
Hideaki
H
D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D000939:Epitopes / Q000276:immunology; D020869:Gene Expression Profiling; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; D006801:Humans; D007167:Immunotherapy; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012097:Repressor Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D016335:Zinc Fingers
D000951:Antigens, Neoplasm; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; C438506:HLA-A*24:02 antigen; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases