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Identification of Multiple HLA-DR-Restricted Epitopes of the Tumor-Associated Antigen CAMEL by CD4⁺ Th1/Th2 Lymphocytes

Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

CD4⁺ Th cells play an important role in the induction and maintenance of adequate CD8⁺ T cell-mediated antitumor responses. Therefore, identification of MHC class II-restricted tumor antigenic epitopes is of major importance for the development of effective immunotherapies with synthetic peptides. CAMEL and NY-ESO-ORF2 are tumor Ags translated in an alternative open reading frame from the highly homologous LAGE-1 and NY-ESO-1 genes, respectively. In this study, we investigated whether CD4⁺ T cell responses could be induced in vitro by autologous, mature dendritic cells pulsed with recombinant CAMEL protein. The data show efficient induction of CAMEL-specific CD4⁺ T cells with mixed Th1/Th2 phenotype in two healthy donors. Isolation of CD4⁺ T cell clones from the T cell cultures of both donors led to the identification of four naturally processed HLA-DR-binding CAMEL epitopes: CAMEL_1–20, CAMEL_14–33, CAMEL_46–65, and CAMEL_81–102. Two peptides (CAMEL_1–20 and CAMEL_14–33) also contain previously identified HLA class I-binding CD8⁺ T cell epitopes shared by CAMEL and NY-ESO-ORF2 and are therefore interesting tools to explore for immunotherapy. Furthermore, two CD4⁺ T cell clones that recognized the CAMEL_14–33 peptide with similar affinities were shown to differ in recognition of tumor cells. These CD4⁺ T cell clones recognized the same minimal epitope and expressed similar levels of adhesion, costimulatory, and inhibitory molecules. TCR analysis demonstrated that these clones expressed identical TCR -chains, but different complementarity-determining region 3 loops of the TCR -chains. Introduction of the TCRs into proper recipient cells should reveal whether the different complementarity-determining region 3 loops are important for tumor cell recognition.

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