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Rembert Pieper^*, Robert E. Christian, Monica I. Gonzales^*, Michael I. Nishimura^*, Gaorav Gupta^*, Robert E. Settlage, Jeffrey Shabanowitz, Steven A. Rosenberg^*, Donald F. Hunt, and Suzanne L. Topalian^*

From the ^* Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and the Department of Chemistry, University of Virginia, Charlottesville, Virginia 22908

CD4⁺ T cells play a critical role in generating and maintaining immune responses against pathogens and alloantigens, and evidence suggests an important role for them in antitumor immunity as well. Although major histocompatibility complex class II–restricted human CD4⁺ T cells with specific antitumor reactivities have been described, no standard method exists for cloning the recognized tumor-associated antigen (Ag). In this study, biochemical protein purification methods were used in conjunction with novel mass spectrometry sequencing techniques and molecular cloning to isolate a unique melanoma Ag recognized by a CD4⁺ tumor-infiltrating lymphocyte (TIL) line. The HLA-DRβ1*0101–restricted Ag was determined to be a mutated glycolytic enzyme, triosephosphate isomerase (TPI). A C to T mutation identified by cDNA sequencing caused a Thr to Ile conversion in TPI, which could be detected in a tryptic digest of tumor-derived TPI by mass spectrometry. The Thr to Ile conversion created a neoepitope whose T cell stimulatory activity was enhanced at least 5 logs compared with the wild-type peptide. Analysis of T cell recognition of serially truncated peptides suggested that the mutated amino acid residue was a T cell receptor contact. Defining human tumor Ag recognized by T helper cells may provide important clues to designing more effective immunotherapies for cancer.

Key Words: melanoma • antigen • CD4⁺ T cells • HLA-DR1 • triosephosphate isomerase

¹ Abbreviations used in this paper: ID, inner diameter; MART, melanoma antigen recognized by T cells; µESI, microelectrospray ionization; MS, mass spectrometry; OD, outer diameter; TIL, tumor-infiltrating lymphocyte(s); TPI, triosephosphate isomerase.

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