HLA class I - associated immunodominance affects CTL responsiveness to an ESO recombinant protein tumor antigen vaccine.
OBJECTIVE
Vaccination with full-length human tumor antigens aims at inducing or increasing antitumor immune responses, including CD8 CTL in cancer patients across the HLA barrier. We have recently reported that vaccination with a recombinant tumor-specific NY-ESO-1 (ESO) protein, administered with Montanide and CpG resulted in the induction of specific integrated antibody and CD4 T cell responses in all vaccinated patients examined, and significant CTL responses in half of them. Vaccine-induced CTL mostly recognized a single immunodominant region (ESO 81-110). The purpose of the present study was to identify genetic factor(s) distinguishing CTL responders from nonresponders.


METHODS
We determined the HLA class I alleles expressed by CTL responders and nonresponders using high-resolution molecular typing. Using short overlapping peptides spanning the ESO immunodominant CTL region and HLA class I/ESO peptide tetramers, we determined the epitopes recognized by the majority of vaccine-induced CTL.


RESULTS
CTL induced by vaccination with ESO protein mostly recognized distinct but closely overlapping epitopes restricted by a few frequently expressed HLA-B35 and HLA-Cw3 alleles. All CTL responders expressed at least one of the identified alleles, whereas none of the nonresponders expressed them.


CONCLUSIONS
Expression of HLA-B35 and HLA-Cw3 is associated with the induction of immunodominant CTL responses following vaccination with recombinant ESO protein. Because recombinant tumor-specific proteins are presently among the most promising candidate anticancer vaccines, our findings indicate that the monitoring of cancer vaccine trials should systematically include the assessment of HLA association with responsiveness.
Bioley
Gilles
G
Institut National de la Santé et de la Recherche Médicale, U892, CLCC René Gauducheau, Saint Herblain, France.
Guillaume
Philippe
P
Luescher
Immanuel
I
Yeh
Alice
A
Dupont
Bo
B
Bhardwaj
Nina
N
Mears
Gregory
G
Old
Lloyd J
LJ
Valmori
Danila
D
Ayyoub
Maha
M
D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D015797:HLA-B35 Antigen / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D015797:HLA-B35 Antigen; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D014614:Vaccines, Synthetic