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 3

ABabDR4-derived TCRs recognized NY-ESO-1 more efficiently than human-derived TCRs.

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ABabDR4-derived TCRs recognized NY-ESO-1 more efficiently than human-der...
(A) Protein lysates from cell lines used for coculture experiments in C and D were assessed for the presence of NY-ESO-1 protein. β-Actin was stained as protein loading control. (B) Melanoma cell lines pretreated with IFN-γ and the LCL BSM were stained for HLA-DR (dark gray) or isotype control (light gray) and were measured by flow cytometry. (C and D) TCR-transduced CD4+ T cells were cocultured with the LCL BSM (HLA-DR4+) and the melanoma cell lines FM3 (NY-ESO-1–, HLA-DR4+), FM6 (NY-ESO-1+, HLA-DR4–), FM82, and FM56 (NY-ESO-1+, HLA-DR4+). Cell lines FM3-NY and BSM-NY were transduced to express NY-ESO-1; BSM was transduced with mCherry (BSM-mCh) as a control. NY-ESO-1116 (NY116), PMA and ionomycin (P/I), and blocking antibody αHLA-DR or αHLA-ABC were added where indicated. After overnight incubation, IFN-γ or IL-2 was measured in the supernatant. Mean values of intra-assay duplicates with SD are shown. The results are representative of 3 independent experiments performed with PBLs from different donors (B, C, and D).