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Immunogenicity without Immunoselection: A Mutant but Functional Antioxidant Enzyme Retained in a Human Metastatic Melanoma and Targeted by CD8⁺ T Cells with a Memory Phenotype

Units of ¹ Immunobiology of Human Tumors and ² Immunotherapy of Human Tumors, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, Milan, Italy

Requests for reprints: Marialuisa Sensi, Unit of Immunobiology of Human Tumors, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-23902633; Fax: 39-02-23902630; E-mail: marialuisa.sensi{at}istitutotumori.mi.it.

Human melanomas can express unique tumor antigens, resulting from mutated proteins, and shared epitopes encoded for by normal genes, but these two classes of antigens have not been previously compared for immunogenicity and retention in metastatic cells. Here, we identified a new unique antigen generated by a point mutation in the peroxiredoxin 5 (Prdx5) gene in an HLA-A*0201⁺ human metastatic melanoma lacking the wild-type allele. An antioxidant assay, with recombinant Prdx5 proteins, and evaluation of peroxide accumulation in transiently transfected cells, indicated that the mutant protein retained its enzymatic activity. The mutation in the Prdx5 protein did not generate a new HLA agretope but yielded an HLA-A*0201–restricted T cell epitope (Prdx5_110-119). By HLA-tetramer analysis, in a tumor-invaded lymph node, >50% of mutant Prdx5-specific CD8⁺ T cells (frequency 0.37%/CD8⁺) showed a CCR7^+/– CD45RA^– "T_CM" or "T_EM" phenotype, as found in Melan-A/MART-1–specific T cells (frequency 0.68%/CD8⁺) in the same tissue. In agreement with their memory phenotype, the Prdx5-specific T cells readily expanded in vitro in mixed lymphocyte-tumor culture, as did the Melan-/MART-1–specific T cells. By immunohistochemistry of the invaded lymph node, the mutant Prdx5 protein was expressed in all neoplastic cells, in contrast with the heterogeneous expression of shared antigens as Melan-A/MART-1, gp100 and tyrosinase. Thus, a unique tumor antigen can be as immunogenic as the melanoma differentiation antigens but, in contrast to the latter, may be retained in all metastatic cells possibly as result of the relevant cellular function exerted by the mutated protein.

Key Words: tumor antigen • T cell immunity • oxidative stress • peroxiredoxin 5 • HLA/peptide tetramers

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