DNA sequence analysis of T-cell receptor genes reveals an oligoclonal T-cell response to a tumor with multiple target antigens (original) (raw)
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International Journal of Cancer, 1994
To see whether different antigens expressed by the same tumor are recognized by distinct T-cell receptors (TCR), we used cytotoxic T-lymphocyte (CTL) lines known to lyse in vitro the syngeneic BALB/c adenocarcinoma C-26. Four of these CD3+ CD8+ lines showed 4 different patterns of lysis on a panel of MHC-class-I-compatible targets. The activity was H-2drestricted and could be blocked by antLCD3 and anti-TCR-dP monoclonal antibodies (MAbs). The CTL lines were also effective, although to a different extent, in adoptive immunotherapy of mice bearing lung metastases. Phenotypic analysis revealed in all the lines a high frequency of cells positive for CD45, asialo GM I (ASGM I), lymphocyte-function-associated antigen-I (LFA-I), intercellular adhesion molecule-I (ICAM-I) and CD44, but negligible expression of L-selectin (LAM-I) and very late antigen-4 (VLA-4); 2 lines expressed the vitronectin-receptor (VN-R). Analysis of TCR VP-chains used by the 4 lines showed selective presence of Vp6, Vp8.2, Vp8.3 and of Vp13 chains. MAbs directed to these Vf3 chains blocked their lytic activity in vitro. Va-chain transcripts of the lines were identified by polymerase chain reaction (PCR) as VolllTl I and Va52 in 2 lines, while one could not be identified. Analysis of Vps in mixed lymphocyte-tumor-cell cultures (MLTC) of T cells deriving from tumor-infiltrating lymphocytes (TlL) or from spleen of C-26 tumor-bearing or immune animals indicated that the TCR of the CTL lines were representatives of the TCR repertoire recognizing C-26 tumor, since their Vps were shown to be selectively expanded in MLTC. o I994 Wiley-Liss, Inc.
Identification of Genes Coding for Tumor Antigens Recognized by Cytolytic T Lymphocytes
Methods, 1997
Strategies have been developed to characterize tumor antigens recognized by cytolytic T lymphocytes (CTL). We use a genetic approach based on the transfection of HLA genes and cDNA libraries in COS cells to isolate the gene producing the antigenic peptide. The tumor-specific expression of this gene can be evaluated by cDNA synthesis and quantitative PCR amplification. Transfection of fragments of the isolated gene allows the identification of the region encoding the antigenic peptide. Peptides are synthesized and tested for their ability to sensitize target cells to lysis by the CTL.
The Journal of experimental medicine, 1995
Peptide MAGE-1.A1 is a nonamer derived from protein MAGE-1 that can associate with the HLA-A1 molecule. It was shown previously to be recognized by an antitumor cytolytic T lymphocyte (CTL) clone derived from the blood of melanoma patient MZ2. We derived two other anti-MAGE-1.A1 CTL clones from different blood samples of the same patient and compared the fine specificity of recognition of the three CTL by testing them on variant MAGE-1.A1 peptides incorporating different amino acid substitutions. The epitopes recognized by the CTL proved to be different. While modifications of residues at positions 5, 6, or 7 in the antigenic peptide affected recognition by the three CTL, each of the modifications of residues at positions 1, 4, or 8 affected recognition by one CTL only. The sequences of both the alpha and beta chains of the T cell antigen receptor of the three CTL were completely different. The results indicate a long-lasting diversity in terms of fine specificity and of T cell anti...
Oligoclonal T cells in human cancer
Medical Oncology, 1998
Many solid tumors are characterised by the infiltration of lymphocytes and their presence has been correlated with a more favourable prognosis. These tumor-infiltrating lymphocytes (TIL), have been shown to possess specific cytolytic reactivity towards autologous tumours, thus suggesting that tumour cells may express antigens capable of eliciting an immune response. Expression of such tumour-associated antigens (TAA) in combination with appropriate accessory signals would lead to the in vivo accumulation of T cells with anti-tumour specificity. Analysis of the composition of the specific T-cell receptor (TCR) of TIL could thus provide information on the nature of the antigen(s) recognised by TIL. In this review, different aspects of the presence of clonal T cells in patients with cancer are discussed.
Cancer Research, 2012
The accumulation of CD4 + T regulatory cells (Treg) in tumor tissue is a widely described phenomenon in mouse models and in human cancer patients. Understanding the mechanisms by which Treg migrate and accumulate in tumors is important because they strongly influence the potential efficacy of many immunotherapies. In this study, we used immunoscope technology to analyze the T-cell receptor (TCR) repertoire of tumor-infiltrating T cells in non-TCR transgenic mice. Both tumor-infiltrating Tregs and T effector cells (Teff) displayed sequence profiles in the CDR3 region which were characteristic of biased repertoires seen during clonal cell expansions, implying that strong T-cell responses have occurred within the tumor tissue. By comparing the TCR sequences of tumor-infiltrating Tregs, we obtained evidence of the presence of so-called public TCR sequences that are common to many individuals yet were tumor-specific in nature. Such comparisons also suggested that the Treg-Teff conversion process is not an active process at the tumor site or tumor-draining lymph nodes. Our findings strongly suggest that Treg infiltration of tumor tissue is followed by marked proliferation of a few dominant T cell clones in the tumor.
Cellular immunity and the immunotherapy of cancer
Journal of Cellular Biochemistry, 1990
Thymocytes bearing T cell antigen receptors (TCR) with different Vy segments appear in an ordered manner during fetal development in the mouse. Vy3, borne by the first wave of TCR+ cells to appear in ontogeny, is in the adult mouse found only in the skin, where it is expressed by the vast malority of the T cells. Thymus grafting experiments and in utero antibody treatment confirm that the epidermis-associated T cells arise from precursors found only in the fetal thymus. A consequence of this early fetal origin is a restricted TCR repertoire of the epidermal T cells. Each of several clones as well as polyclonal cell preparations were found to have identical TCR composed of Vy3JylCyl and V61D62C6 gene segments, with essentially no junctional diversity. This observation suggests that these cells might function in trauma signal surveillance, rather than surveillance for foreign antigen. T cells associated with another epithelial tissue, the gut, were found to be similarly restricted in Vy usage to Vy5, but expressed several different V6 segments. The gut associated TCR were found to have extreme ]unctiondl variability, suggesting that they arose later in ontogeny and are suited for foreign antigen surveillance. In mice transgenic for the skin TCR, gut T cells expressed only the transgenic TCR, indicating that the TCR is not involved in tissue homing.
International Journal of Cancer, 2011
We previously showed that exposure to UV radiation after immunization suppresses Th1 and Th2 immune responses, leading to impaired Ab and allo-immune responses, but the impact of UV radiation after immunization on anti-tumor immune responses mediated by tumor-specific CD8 1 T cell responses remains less clear. Furthermore, the exact phenotypic and functional characteristics of regulatory T cell population responsible for the UV-induced immunosuppression still remain elusive. Using the MBL-2 lymphoma cell line engineered to express OVA as a surrogate tumor Ag, here we demonstrate that UV irradiation after tumor Ag-immunization suppresses the anti-tumor immune response in a manner dependent on the immunizing Ag. This suppression was mediated by interleukin (IL)-10 released from CD4 1 CD25 1 T cells, by which impaired the induction of cytotoxic T lymphocytes (CTL) able to kill Ag-expressing tumor cells. In addition, we generated a panel of T cell clones from UV-irradiated and non-irradiated mice, and all of the clones derived from UV-irradiated mice had a Tr1-type regulatory T cell phenotype with expression of IL-10 and c-Maf, but not Foxp3. These Tr1-type regulatory T cell clones suppressed tumor rejection in vivo as well as Th cell activation in vitro in an IL-10 dependent manner. Given that suppression of Ag-specific CTL responses can be induced in Ag-sensitized mice by UV irradiation, our results may imply that exposure to UV radiation during premalignant stage induces tumor-Ag specific Tr1 cells that mediate tumor-Ag specific immune suppression resulting in the promotion of tumor progression.