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HLA class I-redirected anti-tumour CD4+T-cells require a higher TCR binding affinity for optimal activity than CD8+T-cells

Tan, M., Dolton, Garry Michael, Gerry, Andrew B., Brewer, Joanna E., Bennett, Alan D., Pumphrey, Nick, Jakobsen, Bent K. and Sewell, Andrew K. 2017. HLA class I-redirected anti-tumour CD4+T-cells require a higher TCR binding affinity for optimal activity than CD8+T-cells. Clinical and Experimental Immunology 187 (1) , pp. 124-137. 10.1111/cei.12828

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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 leukocyte 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 coreceptor 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 wildtype 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 optimised for CD8+ T-cells is below par and that there is room for substantial improvement. This article is protected by copyright. All rights reserved.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: Immunotherapy; CD4+ T-cells; TCR affinity; MHC Class I
Publisher: Wiley-Blackwell
ISSN: 0009-9104
Funders: Wellcome Trust
Date of First Compliant Deposit: 18 August 2016
Date of Acceptance: 16 June 2016
Last Modified: 27 Nov 2017 22:12
URI: http://orca-mwe.cf.ac.uk/id/eprint/93910

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