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A Mycoplasma Peptide Elicits Heteroclitic CD4⁺ T Cell Responses against Tumor Antigen MAGE-A6

Authors' Affiliations: Departments of ¹ Immunology, ² Dermatology, ³ Surgery, and ⁴ Medicine, University of Pittsburgh School of Medicine, and ⁵ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Walter J. Storkus, Department of Dermatology, University of Pittsburgh Medical Center, W1041.2 Biomedical Sciences Tower, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-648-9981; Fax: 412-383-5857; E-mail: storkuswj{at}upmc.edu.

Purpose: 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.

Experimental Design: 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 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.