PubMed · 9789599
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S A Pileri, S Ascani, E Sabattini, B Falini. 1998. Peripheral T-cell lymphoma: a developing concept.. https://doi.org/10.1023/a%3A1008414002612
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Immunization with wild-type sequence (wt) p53 epitopes represents a novel therapeutic strategy for cancer patients with tumors accumulating mutant p53. To evaluate usefulness of p53-derived peptides as future cancer vaccines, frequencies of wt p53(264-272) peptide-specific CD8+ T cells were determined in the peripheral circulation of patients with squamous cell carcinoma of the head and neck (SCCHN). T cells of 30 HLA-A2.1+ patients and 31 HLA-A2.1+ healthy individuals were evaluated by multicolor flow cytometry analysis using peptide-HLA-A2.1 complexes (tetramers). T cells specific for an influenza matrix peptide (a model recall antigen) or an HIV reverse transcriptase peptide (a model novel antigen) were studied in parallel. Patients with SCCHN had a significantly higher mean frequency of CD8+ T cells specific for wt p53(264-272) than normal donors (P = 0.0041). Surprisingly, the frequency of epitope-specific T cells in the circulation of patients did not correlate with p53 accumulation in the tumor. In patients whose tumors had normal p53 expression or had p53 gene mutations preventing presentation of this epitope, high frequencies of wt p53(264-272)-specific CD8+ T cells were found, of which many were memory T cells. In contrast, patients whose tumors accumulated p53 had low frequencies of wt p53(264-272)-specific CD8+ T cells, which predominantly had a naive phenotype and were unable to proliferate ex vivo in response to the epitope, as reported by us previously (T. K. Hoffmann, J. Immunol., 165: 5938-5944, 2000). This seemingly contradictory relationship between the high frequency of epitope-specific T cells and wt p53 expression in the tumor suggests that other factors may contribute to the observed anti-p53 responses. Human papillomavirus-16 E6/E7 expression is common in SCCHN, and E6 is known to promote presentation of wt p53 epitopes. Although human papillomavirus-16 E6/E7 expression was detected in 46% of the tumors, it did not correlate with the frequency of wt p53(264-272)-specific CD8+ T cells or with p53 expression in the tumor. These findings emphasize the complexity of interactions between the tumor and the host immune system, and, thus, have particularly important implications for future p53-based immunization strategies.
The molecular characterization of antigens preferentially or exclusively expressed by astrocytomas and recognized by the autologous immune system are a prerequisite for the development of specific vaccines. To identify such antigens, we screened 5 cDNA expression libraries derived from astrocytomas and other gliomas for reactivity with high-titered IgG antibodies in the sera of astrocytoma patients using SEREX, the serologic identification of antigens by recombinant cDNA expression cloning. Autologous and allogeneic SEREX analysis of >5 x 10(6) clones with the sera of 18 astrocytoma patients revealed 10 antigens: the differentiation antigen glial fibrillary acidic protein (GFAP), Bax-inhibitor 1 (which was overexpressed in all glioma samples tested), 3 other molecules involved in the regulation of gene expression and proliferation (the nm23-H2-encoded nucleoside diphosphate kinase B, the Ran binding protein-2 and a DNA binding protein encoded by the son gene), SP40,40 (a complement inhibitory molecule), the chaperonin TCP-1, calnexin and 2 new gene products. No immune responses were detected against the "shared tumor" or "cancer testis antigens" that are regularly expressed in gliomas. Antibody responses in astrocytoma patients against antigens expressed by gliomas were rare and, with the exception of Bax-inhibitor 1 and the product of the son gene, were also found in apparently healthy controls. We conclude that although astrocytomas express a broad spectrum of antigens, they elicit antibody responses only rarely, most likely because of their intrinsic immunosuppressive effects.
A practical mixed hemadsorption assay (MHA) was developed for the detection of cell surface binding anti-tumor antigen antibodies (anti-TA Ab) in the human sera. The assay was compared to enzyme-linked immunosorbent assay (ELISA) and dot ELISA in the detection of the antibodies developed against GA733-2 antigen. SW1116 cell line and recombinant GA733-2E protein were used as targets in the MHA and solid phase immunoassays (SPIA), respectively. Sera were obtained from healthy donors and vaccinated-colon carcinoma patients. The sensitivity level of the MHA was very high for detection of anti-TA Ab in sera.