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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 December 10, 2018
Citation Information: J Clin Invest. 2019;129(1):324-335. https://doi.org/10.1172/JCI120391.
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Research Article Immunology Oncology

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

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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 5

ABabDR4-derived TCR-3598_2 showed no alloreactivity.

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ABabDR4-derived TCR-3598_2 showed no alloreactivity.
TCR-transduced CD4+...
TCR-transduced CD4+ T cells were cocultured with a panel of LCLs expressing different MHC class I and II molecules (Supplemental Table 1). As a positive control, PMA and ionomycin were added to the T cells. After overnight incubation, IL-2 was measured in the supernatant. Background, defined as the highest cytokine secretion observed for untransduced T cells, is indicated by the dotted line. Mean values of intra-assay duplicates with SD are shown. In the grid below, cross-reactions to LCLs are marked by an X. The results are representative of 3 independent experiments performed with PBLs from different donors. See also Supplemental Figure 3.
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