Human leukocyte antigen-A2-restricted CTL responses to mutated BRAF peptides in melanoma patients.
Mutated BRAF (BRAF(V600E)) is a potential immunotherapeutic target for melanoma because of its tumor specificity and expression in the majority of these lesions derived from different patients. BRAF(V600E) is expressed intracellularly and not on the cell surface, therefore providing a target for T cells but not B cells. Demonstration of patients' T cell responses to BRAF(V600E) would suggest the feasibility of active specific immunotherapy targeting the mutation in these patients. In the present study, BRAF(V600E) peptides with putative binding sites for human leukocyte antigen (HLA)-A2 were used to stimulate T lymphocytes of HLA-A2-positive melanoma patients. Four of five patients with BRAF(V600E)-positive lesions showed lymphoproliferative responses to BRAF(V600E) peptide stimulation. These responses were specific for the mutated epitope and HLA-A2 was restricted in three patients. Lymphocytes from these three patients were cytotoxic against HLA-A2-matched BRAF(V600E)-positive melanoma cells. None of the four patients with BRAF(V600E)-negative lesions and none of five healthy donors had lymphoproliferative responses specific for the mutated epitope. The high prevalence (approximately 50%) of HLA-A2 among melanoma patients renders HLA-A2-restricted BRAF(V600E) peptides attractive candidate vaccines for these patients.
The Wistar Institute, Philadelphia, PA 19104, USA.
Rajasekharan
R
Somasundaram
Rolf
R
Swoboda
Laura
L
Caputo
Laszlo
L
Otvos
Barbara
B
Weber
Patricia
P
Volpe
Patricia
P
van Belle
Susan
S
Hotz
David E
DE
Elder
Francesco M
FM
Marincola
Lynn
L
Schuchter
DuPont
D
Guerry
Brian J
BJ
Czerniecki
Dorothee
D
Herlyn
D001665:Binding Sites; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf