Lysis of MYCN-amplified neuroblastoma cells by MYCN peptide-specific cytotoxic T lymphocytes.
The effectiveness of cell-mediated immunotherapy for cancer can be limited by loss-of-antigen mutations that occur during tumor growth. In neuroblastoma, amplification of the MYCN oncogene correlates with rapid tumor progression and a poor prognosis overall. We propose that the MYCN protein, the high-level expression of which is required for maintenance of the malignant phenotype, would be an ideal target for vaccine therapy. The MYCN-derived S9K peptide (amino acids 7-15; STMPGMICK), which contains an HLA-A1 binding motif, was used to generate CTLs from the peripheral blood lymphocytes of an HLA-A1+ healthy donor and an HLA-A1+ patient with MYCN-amplified neuroblastoma These CTL lines specifically lysed HLA-matched, MYCN-amplified neuroblastoma tumor cells. They did not lyse either HLA-mismatched, MYCN-amplified, or matched/nonmatched, non-MYCN-amplified tumor cells. The CTL activity was inhibited by a monoclonal antibody to a class I HLA monomorphic determinant but not by one specific for HLA class II, consistent with a class I-restricted mechanism of cytotoxicity. Antibodies to CD8, but not those to CD4, also inhibited CTL activity, identifying CD8+ lymphocytes as the effector cell population. These results show that MYCN-derived peptides can serve as tumor-specific antigens and suggest a rational approach to cell-mediated immunotherapy for MYCN-amplified neuroblastoma.
Sarkar
A K
AK
Department of Surgery, Baylor College of Medicine, and Texas Children's Cancer Center, Texas Children's Hospital, Houston 77030-2399, USA.
Nuchtern
J G
JG
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002648:Child; D003602:Cytotoxicity, Immunologic; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc; D015788:HLA-A1 Antigen / Q000276:immunology; D006801:Humans; D007223:Infant; D008297:Male; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015788:HLA-A1 Antigen; D010446:Peptide Fragments; D016271:Proto-Oncogene Proteins c-myc