Chronic TCR-MHC (self)-interactions limit the functional potential of TCR affinity-increased CD8 T lymphocytes.

Details

Serval ID
serval:BIB_F1677E168BF3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Chronic TCR-MHC (self)-interactions limit the functional potential of TCR affinity-increased CD8 T lymphocytes.
Journal
Journal for immunotherapy of cancer
Author(s)
Duong M.N., Erdes E., Hebeisen M., Rufer N.
ISSN
2051-1426 (Electronic)
ISSN-L
2051-1426
Publication state
Published
Issued date
05/11/2019
Peer-reviewed
Oui
Volume
7
Number
1
Pages
284
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Affinity-optimized T cell receptor (TCR)-engineered lymphocytes targeting tumor antigens can mediate potent antitumor responses in cancer patients, but also bear substantial risks for off-target toxicities. Most preclinical studies have focused on T cell responses to antigen-specific stimulation. In contrast, little is known on the regulation of T cell responsiveness through continuous TCR triggering and consequent tonic signaling. Here, we addressed the question whether increasing the TCR affinity can lead to chronic interactions occurring directly between TCRs and MHC-(self) molecules, which may modulate the overall functional potency of tumor-redirected CD8 T cells. For this purpose, we developed two complementary human CD8 T cell models (i.e. HLA-A2 knock-in and knock-out) engineered with incremental-affinity TCRs to the HLA-A2/NY-ESO-1 tumor antigen.
The impact of HLA-A2 recognition, depending on TCR affinity, was assessed at the levels of the TCR/CD3 complex, regulatory receptors, and signaling, under steady-state conditions and in kinetic studies. The quality of CD8 T cell responses was further evaluated by gene expression and multiplex cytokine profiling, as well as real-time quantitative cell killing, combined with co-culture assays.
We found that HLA-A2 per se (in absence of cognate peptide) can trigger chronic activation followed by a tolerance-like state of tumor-redirected CD8 T cells with increased-affinity TCRs. HLA-A2 <sup>pos</sup> but not HLA-A2 <sup>neg</sup> T cells displayed an activation phenotype, associated with enhanced upregulation of c-CBL and multiple inhibitory receptors. T cell activation preceded TCR/CD3 downmodulation, impaired TCR signaling and functional hyporesponsiveness. This stepwise activation-to-hyporesponsive state was dependent on TCR affinity and already detectable at the upper end of the physiological affinity range (K <sub>D</sub> ≤ 1 μM). Similar findings were made when affinity-increased HLA-A2 <sup>neg</sup> CD8 T cells were chronically exposed to HLA-A2 <sup>pos</sup> -expressing target cells.
Our observations indicate that sustained interactions between affinity-increased TCR and self-MHC can directly adjust the functional potential of T cells, even in the absence of antigen-specific stimulation. The observed tolerance-like state depends on TCR affinity and has therefore potential implications for the design of affinity-improved TCRs for adoptive T cell therapy, as several engineered TCRs currently used in clinical trials share similar affinity properties.
Keywords
Antigens, Neoplasm/immunology, CD3 Complex/metabolism, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Cell Line, Tumor, Cytotoxicity, Immunologic, Gene Expression, HLA-A2 Antigen/genetics, HLA-A2 Antigen/immunology, HLA-A2 Antigen/metabolism, Humans, Immunophenotyping, Immunotherapy, Adoptive, Lymphocyte Activation/immunology, Neoplasms/etiology, Neoplasms/metabolism, Neoplasms/therapy, Protein Binding, Receptors, Antigen, T-Cell/genetics, Receptors, Antigen, T-Cell/metabolism, Receptors, Chimeric Antigen/genetics, Receptors, Chimeric Antigen/metabolism, Signal Transduction, CD8 T cells, Immunotherapy, NY-ESO-1 tumor antigen, Preclinical study, Receptor signaling, T cell activation, T cell function, TCR affinity optimization, TCR/CD3 complex
Pubmed
Web of science
Open Access
Yes
Create date
07/11/2019 23:33
Last modification date
25/07/2020 6:19
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