Stringent allele/epitope requirements for MART-1/Melan A immunodominance

Implications for peptide-based immunotherapy

Maria Bettinotti, Christina J. Kim, Kang Hun Lee, Matthew Roden, Janice N. Cormier, Monica Panelli, Kenneth K. Parker, Francesco M. Marincola

Research output: Contribution to journalArticle

Abstract

The exclusiveness of the relationship between peptide and HLA alleles, combined with their extensive polymorphism, emphasizes the need for immunization strategies based on endogenous processing of full length proteins (containing multiple epitopic determinants) for presentation to T cells. This could allow vaccination regardless of the patient's HLA phenotype, assuming that individual molecules can be efficient T cell Ags in association with various HLA alleles. An endogenous system of Ag presentation was developed using dendritic cells infected with recombinant viral vectors expressing the melanoma-associated Ag MART-1/ Melan A. CD8+ T cells from melanoma patients were activated in vitro by coincubation with infected dendritic cells and tested for recognition of HLA-A-matched melanoma targets. This allowed the analysis of T cell induction in association with any HLA-A allele of a given patient's phenotype. In this system, MART-1/Melan A could not efficiently immunize in association with HLA-A alleles other than A*0201, including the one residue variant from A*0201: HLA-A*0226. Clonal analysis of MART-1/Melan A-specific CTL confirmed that MART-1/Melan A immunodominance is strongly restricted to the AAGIGILTV/HLA-A*0201 combination. The stringent epitope/allele requirements for MART-1/Melan A/TCR interactions were not associated with limitations in the TCR repertoire. In conclusion, autologous induction of MART-1/Melan A CTL by whole Ag processing and presentation is restricted to a unique allele/ligand combination and is excluded by minimal changes in HLA structure. Thus, whole protein vaccination for small m.w. Ags may provide no further advantage over a peptide-based approach.

Original languageEnglish (US)
Pages (from-to)877-889
Number of pages13
JournalJournal of Immunology
Volume161
Issue number2
StatePublished - Jul 15 1998
Externally publishedYes

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MART-1 Antigen
Immunotherapy
Epitopes
Alleles
Peptides
HLA-A Antigens
T-Lymphocytes
Melanoma
Dendritic Cells
Vaccination
Phenotype
Immunization
Proteins
Ligands
HLA-A*02:01 antigen

ASJC Scopus subject areas

  • Immunology

Cite this

Bettinotti, M., Kim, C. J., Lee, K. H., Roden, M., Cormier, J. N., Panelli, M., ... Marincola, F. M. (1998). Stringent allele/epitope requirements for MART-1/Melan A immunodominance: Implications for peptide-based immunotherapy. Journal of Immunology, 161(2), 877-889.

Stringent allele/epitope requirements for MART-1/Melan A immunodominance : Implications for peptide-based immunotherapy. / Bettinotti, Maria; Kim, Christina J.; Lee, Kang Hun; Roden, Matthew; Cormier, Janice N.; Panelli, Monica; Parker, Kenneth K.; Marincola, Francesco M.

In: Journal of Immunology, Vol. 161, No. 2, 15.07.1998, p. 877-889.

Research output: Contribution to journalArticle

Bettinotti, M, Kim, CJ, Lee, KH, Roden, M, Cormier, JN, Panelli, M, Parker, KK & Marincola, FM 1998, 'Stringent allele/epitope requirements for MART-1/Melan A immunodominance: Implications for peptide-based immunotherapy', Journal of Immunology, vol. 161, no. 2, pp. 877-889.
Bettinotti, Maria ; Kim, Christina J. ; Lee, Kang Hun ; Roden, Matthew ; Cormier, Janice N. ; Panelli, Monica ; Parker, Kenneth K. ; Marincola, Francesco M. / Stringent allele/epitope requirements for MART-1/Melan A immunodominance : Implications for peptide-based immunotherapy. In: Journal of Immunology. 1998 ; Vol. 161, No. 2. pp. 877-889.
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