Effective NY-ESO-1–specific MHC II–restricted T cell receptors from antigen-negative hosts enhance tumor regression
Lucia Poncette, … , Felix K.M. Lorenz, Thomas Blankenstein
Lucia Poncette, … , Felix K.M. Lorenz, Thomas Blankenstein
Published January 2, 2019; First published December 10, 2018
Citation Information: J Clin Invest. 2019;129(1):324-335. https://doi.org/10.1172/JCI120391.
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Categories: Research Article Immunology Oncology

Effective NY-ESO-1–specific MHC II–restricted T cell receptors from antigen-negative hosts enhance tumor regression

Abstract

Adoptive transfer of T cell receptor–engineered (TCR-engineered) T cells is a promising approach in cancer therapy but needs improvement for more effective treatment of solid tumors. While most clinical approaches have focused on CD8+ T cells, the importance of CD4+ T cells in mediating tumor regression has become apparent. Regarding shared (self) tumor antigens, it is unclear whether the human CD4+ T cell repertoire has been shaped by tolerance mechanisms and lacks highly functional TCRs suitable for therapy. Here, TCRs against the tumor-associated antigen NY-ESO-1 were isolated either from human CD4+ T cells or from mice that express a diverse human TCR repertoire with HLA-DRA/DRB1*0401 restriction and are NY-ESO-1 negative. NY-ESO-1–reactive TCRs from the mice showed superior recognition of tumor cells and higher functional activity compared with TCRs from humans. We identified a candidate TCR, TCR-3598_2, which was expressed in CD4+ T cells and caused tumor regression in combination with NY-ESO-1–redirected CD8+ T cells in a mouse model of adoptive T cell therapy. These data suggest that MHC II–restricted TCRs against NY-ESO-1 from a nontolerant nonhuman host are of optimal affinity and that the combined use of MHC I– and II–restricted TCRs against NY-ESO-1 can make adoptive T cell therapy more effective.

Authors

Lucia Poncette, Xiaojing Chen, Felix K.M. Lorenz, Thomas Blankenstein

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Figure 1

NY-ESO-1–reactive TCRs generated from ABabDR4 mice.

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NY-ESO-1–reactive TCRs generated from ABabDR4 mice. (A) PBLs from an ABa...
(A) PBLs from an ABabDR4 mouse immunized with NY-ESO-1116 peptide or NY-ESO-1 DNA were pulsed with NY-ESO-1116 or irrelevant peptide and were stained intracellularly after overnight incubation. The results shown are representative of >10 (Peptide imm.) and 3 (DNA imm.) mice. (B) For sorting by flow cytometry, NY-ESO-1–reactive CD4+ T cells were labeled by the IFN-γ capture method following NY-ESO-1116 restimulation (TCR-3598/3598_2) or by DR4/NY-ESO-1116 tetramer staining following a 1-week culture period in the presence of 10–8 M NY-ESO-1116 (TCR-3600 and -5712) or αCD3/CD28 beads (TCR-5713). (C) Splenocytes from an ABabDR4 mouse immunized with NY-ESO-1 DNA were pulsed with NY-ESO-1116 or irrelevant peptide and stained intracellularly after 6 hours of incubation. (D) Human CD4+ T cells were transduced with NY-ESO-1–reactive TCRs isolated from CD4+ T cells shown in B and stained with DR4/NY-ESO-1116 tetramer and for mouse TCRβ constant region (mTCRβ). α and β sequences of NY-ESO-1–reactive TCRs are listed in Table 1. Plotted cells were gated on lymphocytes, live cells, and CD3+ cells (A and B), and CD4+ cells (C and D). Results are representative of 2 independent experiments (C and D). Values represent percentages. See also Supplemental Figure 1.