8 results on '"Pumphrey, N. J."'
Search Results
2. Human leucocyte antigen class I‐redirected anti‐tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells
- Author
-
Tan, M. P., Dolton, G. M., Gerry, A. B., Brewer, J. E., Bennett, A. D., Pumphrey, N. J., Jakobsen, B. K., and Sewell, A. K.
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Receptors, Antigen, T-Cell, alpha-beta ,Translational ,Membrane Proteins ,chemical and pharmacologic phenomena ,Original Articles ,Genetic Therapy ,CD8-Positive T-Lymphocytes ,TCR affinity ,Cancer Vaccines ,Immunotherapy, Adoptive ,CD4+ T cells ,Cell Line ,Antigens, Neoplasm ,Neoplasms ,HLA-A2 Antigen ,MHC class I ,Humans ,Original Article ,immunotherapy ,Transgenes ,Cancer ,Protein Binding ,gp100 Melanoma Antigen - Abstract
Summary CD4+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour‐specific CD4+ T cells occur in low frequency, express relatively low‐affinity T cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leucocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T cells with tumour‐specific HLA class I‐restricted TCRs prior to adoptive transfer. The lack of help from the co‐receptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T cells expressing wild‐type and a range of affinity‐enhanced TCRs specific for the HLA A*0201‐restricted NY‐ESO‐1‐ and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and (ii) optimal TCR binding affinity is higher in CD4+ T cells than CD8+ T cells. These results indicate that the CD4+ T cell component of current adoptive therapies using TCRs optimized for CD8+ T cells is below par and that there is room for substantial improvement.
- Published
- 2016
3. Exploring the molecular interactions of CD31 (PECAM-1) cytoplasmic tail with signalling proteins
- Author
-
Pumphrey, N. J., Young, S. P., and Buckley, C. D.
- Published
- 1998
4. T cell receptor binding affinity governs the functional profile of cancer-specific CD8+T cells
- Author
-
Tan, Mai, Gerry, A. B., Brewer, J. E., Melchiori, L., Bridgeman, John S., Bennett, A. D., Pumphrey, N. J., Jakobsen, B. K., Price, D. A., Ladell, Kristin Ingrid, and Sewell, Andrew K.
- Subjects
RC0254 - Abstract
Antigen-specific T cell receptor (TCR) gene transfer via patient-derived T cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high-affinity tumour-specific TCR clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of T cell-based cancer vaccines and therapeutic strategies that employ naturally generated tumour-specific TCRs. In this study, we used altered peptide ligands and lentivirus-mediated transduction of affinity-enhanced TCRs selected by phage display to study the functional properties of CD8+ T cells specific for three different tumour-associated peptide antigens across a range of binding parameters. The key findings were: (i) TCR affinity controls T cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which T cell function cannot be improved; and (iii) T cells transduced with very high-affinity TCRs exhibit cross-reactivity with self-derived peptides presented by the restricting human leucocyte antigen. Optimal system-defined affinity windows above the range established for natural tumour-specific TCRs therefore allow the enhancement of T cell effector function without off-target effects. These findings have major implications for the rational design of novel TCR-based biologics underpinned by rigorous preclinical evaluation.
- Published
- 2014
5. Human leucocyte antigen class I-redirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells.
- Author
-
Tan, M. P., Dolton, G. M., Gerry, A. B., Brewer, J. E., Bennett, A. D., Pumphrey, N. J., Jakobsen, B. K., and Sewell, A. K.
- Subjects
HLA histocompatibility antigens ,T helper cells ,ANTINEOPLASTIC agents ,IMMUNE response ,PROTEIN expression - Abstract
CD4
+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4+ T cells occur in low frequency, express relatively low-affinity T cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leucocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer. The lack of help from the co-receptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T cells expressing wild-type and a range of affinity-enhanced TCRs specific for the HLA A*0201-restricted NY-ESO-1- and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and (ii) optimal TCR binding affinity is higher in CD4+ T cells than CD8+ T cells. These results indicate that the CD4+ T cell component of current adoptive therapies using TCRs optimized for CD8+ T cells is below par and that there is room for substantial improvement. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
6. T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells.
- Author
-
Tan, M. P., Gerry, A. B., Brewer, J. E., Melchiori, L., Bridgeman, J. S., Bennett, A. D., Pumphrey, N. J., Jakobsen, B. K., Price, D. A., Ladell, K., and Sewell, A. K.
- Subjects
T cell receptors ,GENETIC transformation ,PEPTIDES ,HUMAN T cell receptors ,GENETIC recombination - Abstract
Antigen-specific T cell receptor ( TCR) gene transfer via patient-derived T cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high-affinity tumour-specific TCR clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of T cell-based cancer vaccines and therapeutic strategies that employ naturally generated tumour-specific TCRs. In this study, we used altered peptide ligands and lentivirus-mediated transduction of affinity-enhanced TCRs selected by phage display to study the functional properties of CD8
+ T cells specific for three different tumour-associated peptide antigens across a range of binding parameters. The key findings were: (i) TCR affinity controls T cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which T cell function cannot be improved; and (iii) T cells transduced with very high-affinity TCRs exhibit cross-reactivity with self-derived peptides presented by the restricting human leucocyte antigen. Optimal system-defined affinity windows above the range established for natural tumour-specific TCRs therefore allow the enhancement of T cell effector function without off-target effects. These findings have major implications for the rational design of novel TCR-based biologics underpinned by rigorous preclinical evaluation. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
7. Human leucocyte antigen class I-redirected anti-tumour CD4 + T cells require a higher T cell receptor binding affinity for optimal activity than CD8 + T cells.
- Author
-
Tan MP, Dolton GM, Gerry AB, Brewer JE, Bennett AD, Pumphrey NJ, Jakobsen BK, and Sewell AK
- Subjects
- Antigens, Neoplasm metabolism, Cell Line, Cytotoxicity, Immunologic, Humans, Membrane Proteins metabolism, Neoplasms immunology, Protein Binding, Receptors, Antigen, T-Cell, alpha-beta genetics, Transgenes genetics, gp100 Melanoma Antigen metabolism, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Genetic Therapy methods, HLA-A2 Antigen immunology, Immunotherapy, Adoptive methods, Neoplasms therapy, Receptors, Antigen, T-Cell, alpha-beta metabolism
- Abstract
CD4
+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4+ T cells occur in low frequency, express relatively low-affinity T cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leucocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer. The lack of help from the co-receptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T cells expressing wild-type and a range of affinity-enhanced TCRs specific for the HLA A*0201-restricted NY-ESO-1- and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and (ii) optimal TCR binding affinity is higher in CD4+ T cells than CD8+ T cells. These results indicate that the CD4+ T cell component of current adoptive therapies using TCRs optimized for CD8+ T cells is below par and that there is room for substantial improvement., (© 2016 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)- Published
- 2017
- Full Text
- View/download PDF
8. Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31.
- Author
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Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, and Buckley CD
- Subjects
- Amino Acid Sequence, Binding Sites, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Monocytes metabolism, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phospholipase C gamma, Phosphopeptides metabolism, Phosphorylation, Phosphotyrosine metabolism, Platelet Endothelial Cell Adhesion Molecule-1 chemistry, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, SH2 Domain-Containing Protein Tyrosine Phosphatases, Sequence Homology, Amino Acid, Signal Transduction, Surface Plasmon Resonance, Vanadates pharmacology, src Homology Domains, Isoenzymes metabolism, Phosphoric Monoester Hydrolases metabolism, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Protein Tyrosine Phosphatases metabolism, Type C Phospholipases metabolism
- Abstract
Recent studies have shown that, in addition to its role as an adhesion receptor, platelet endothelial cell adhesion molecule 1/CD31 becomes phosphorylated on tyrosine residues Y663 and Y686 and associates with protein tyrosine phosphatases SHP-1 and SHP-2. In this study, we screened for additional proteins which associate with phosphorylated platelet endothelial cell adhesion molecule 1, using surface plasmon resonance. We found that, besides SHP-1 and SHP-2, platelet endothelial cell adhesion molecule 1 binds the cytoplasmic signalling proteins SHIP and PLC-gamma1 via their Src homology 2 domains. Using two phosphopeptides, NSDVQpY663TEVQV and DTETVpY686SEVRK, we demonstrate differential binding of SHP-1, SHP-2, SHIP and PLC-gamma1. All four cytoplasmic signalling proteins directly associate with cellular platelet endothelial cell adhesion molecule 1, immunoprecipitated from pervanadate-stimulated THP-1 cells. These results suggest that overlapping immunoreceptor tyrosine-based inhibition motif/immunoreceptor tyrosine-based activation motif-like motifs within platelet endothelial cell adhesion molecule 1 mediate differential interactions between the Src homology 2 containing signalling proteins SHP-1, SHP-2, SHIP and PLC-gamma1.
- Published
- 1999
- Full Text
- View/download PDF
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