adenocarcinoma of the prostate ͉ CD4ϩ and͞or CD8 ϩ T cell ͉ cytotoxic T cell ͉ antigen-presenting cell ͉ hormone therapy
Except for melanomas, tumor antigens recognized by cytotoxic T lymphocytes (CTLs) are yet unidentified. We have identified a gene encoding antigenic peptides of human squamous cell carcinomas (SCCs) recognized by human histocompatibility leukocyte antigens (HLA)- A2601–restricted CTLs. This gene showed no similarity to known sequences, and encoded two (125- and 43-kilodalton [kD]) proteins. The 125-kD protein with the leucine zipper motif was expressed in the nucleus of the majority of proliferating cells tested, including normal and malignant cells. The 43-kD protein was expressed in the cytosol of most SCCs from various organs and half of lung adenocarcinomas, but was not expressed in other cancers nor in a panel of normal tissues. The three nonapeptides shared by the two proteins were recognized by the KE4 CTLs, and one of the peptides induced in vitro from peripheral blood mononuclear cells (PBMCs) the CTLs restricted to the autologous tumor cells. The 43-kD protein and this nonapeptide (KGSGKMKTE) may be useful for the specific immunotherapy of HLA-A2601+ epithelial cancer patients.
Lymphocyte infiltration in the retrobulbar space is a prominent histological feature of thyroid-associated ophthalmopathy (TAO). We have characterized phenotypic and functional features of T cells derived from retrobulbar infiltrates of 3 TAO patients to better understand their roles in the disease. One hundred four T-cell clones (TCC) were directly established from cells of retrobulbar tissues using a highly efficient cloning procedure. Phenotypic analysis of TCC showed approximately 70% to 80% were CD3+ CD4+ CD8- T cells, and approximately 20% to 30% were CD3+ CD8+ CD4- T cells. None of the TCC were CD3+ CD4- CD8- T cells. Analysis of the cytokine profile of TCC, as documented by the ability to express interferon-gamma, interleukin (IL)-2, IL-4, and IL-10 demonstrated that the majority of TCC expressed T helper (T(H))1-like profile in both the mRNA and protein levels. A few TCC showed T(H)0-like profile, but no TCC showed T(H)2-like profile. These results suggest that T(H)1-type CD4+ T cells play important roles in the pathogenesis of TAO.
We recently reported the identification of a human SART3 gene that encodes a tumor-rejection antigen recognized by cytotoxic T lymphocytes (CTLs). The squamous-cell carcinoma antigen recognized by T cells-3 (SART3) is an RNAbinding protein expressed in the nucleus of the majority of proliferating cells, including normal cells and malignant cells, but not in normal tissues except for the testes and fetal liver. To determine its biologic function, we employed a 2-hybrid screening in yeast for proteins interacting with SART3, and this method yielded a pre-mRNA splicing factor (RNA-binding protein prevalent during the S phase or RNA-binding protein with a serine-rich domain [RNPS1]) that activated both constitutive and alternative splicing of pre-mRNA in vitro. Interaction of SART3 with RNPS1 through the physical association of N-terminal domains of RNPS1 was confirmed by both in vitro pull-down assay and immunoprecipitation assay. Cotransfection of the 2 genes changed the distribution pattern of SART3 from diffuse nucleoplasmic spreading to nuclear speckled regions in which the RNPS1 was colocalized, suggesting a complex formation of the 2 proteins. In cooperation with RNPS1, SART3 stimulated the proximal alternative 3 splicing of a calcitonin-dihydrofolate reductase chimeric minigene pre-mRNA. These results suggest that SART3 is involved in the regulation of mRNA splicing probably via its complex formation with RNPS1. © 2001 Wiley-Liss, Inc. Key words: tumor-rejection antigens; RNA-binding protein; CTL; immunoprecipitation; 2-hybridOne of the most significant advances in the field of modern tumor immunology has been the identification of genes encoding tumor-rejection antigens that are recognized by HLA-class I-restricted and tumor-specific CTLs. 1 The potential application of these findings to the development of cancer vaccines has raised hopes in the field of immunotherapy for specific cancers. Indeed, several peptides encoded by these genes are now under clinical trials as cancer vaccines, and major tumor regression has been observed in some melanoma patients. 2,3 However, these genes mostly code for self-antigens but not tumor-specific antigens, and most of the biologic functions of these antigens have yet to be discovered. Identification of the biologic functions of these antigens should lead to a better understanding of the molecular basis of T-cell-mediated recognition of self-antigens and also to the discovery of new tumor-rejection antigens. We have reported the identification of a human SART3 gene that encodes a tumorrejection antigen from the cDNA of a human esophageal cancer cell line. 4 The SART3 gene encodes an Mr 140,000 protein expressed in the nucleus of the majority of proliferating cells, including normal and malignant cells. However, it was undetectable in normal tissues except for the testes and fetal liver, regardless of its ubiquitous expression at the mRNA level. 4 The biologic functions of SART3 remain to be elucidated, although this antigen may be critical for ontogenetic development, sin...
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