A mycoplasma peptide elicits heteroclitic CD4+ T cell responses against tumor antigen MAGE-A6.
OBJECTIVE
Although T-helper (Th) epitopes have been previously reported for many tumor antigens, including MAGE-A6, the relevant HLA-DR alleles that present these peptides are expressed by only a minority of patients. The identification of tumor antigenic epitopes presented promiscuously by many HLA-DR alleles would extend the clinical utility of these peptides in vaccines and for the immunomonitoring of cancer patients.


METHODS
A neural network algorithm and in vitro sensitization assays were employed to screen candidate peptides for their immunogenicity.


RESULTS
The MAGE-A6(140-170), MAGE-A6(172-187), and MAGE-A6(280-302) epitopes were recognized by CD4+ T cells isolated from the majority of normal donors and melanoma patients evaluated. Peptide-specific CD4+ T cells also recognized autologous antigen-presenting cell pulsed with recombinant MAGE-A6 (rMAGE) protein, supporting the natural processing and MHC presentation of these epitopes. Given the strong primary in vitro sensitization of normal donor CD4+ T cells by the MAGEA6(172-187) epitope, suggestive of potential cross-reactivity against an environmental stimulus, we identified a highly homologous peptide within the Mycoplasma penetrans HF-2 permease (MPHF2) protein. MPHF2 peptide-primed CD4+ T cells cross-reacted against autologous APC pulsed with the MAGE-A6(172-187) peptide or rMAGE protein and recognized HLA-matched MAGE-A6+ melanoma cell lines. These responses seemed heteroclitic in nature because the functional avidity of MPHF2 peptide-primed CD4+ T cells for the MAGE-A6(172-187) peptide was approximately 1,000 times greater than that of CD4+ T cells primed with the corresponding MAGE-A6 peptide.


CONCLUSIONS
We believe that these novel "promiscuous" MAGE-A6/MPHF2 Th epitopes may prove clinically useful in the treatment and/or monitoring of a high proportion of cancer patients.
Vujanovic
Lazar
L
Department of Immunology, University of Pittsburgh School of Medicine, University Medical Center, Pittsburgh, PA 15213, USA.
Mandic
Maja
M
Olson
Walter C
WC
Kirkwood
John M
JM
Storkus
Walter J
WJ
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018661:Mycoplasma penetrans / Q000276:immunology*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology
D000951:Antigens, Neoplasm; D001426:Bacterial Proteins; D018984:Epitopes, T-Lymphocyte; C095203:MAGEA6 protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D011994:Recombinant Proteins