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

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 2

NY-ESO-1–reactive TCRs generated from CD4+ T cells from human donors.

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NY-ESO-1–reactive TCRs generated from CD4+ T cells from human donors. (A...
(A) PBLs from an HLA-DR4+ donor were enriched by magnetic cell sorting for CD4+ T cells expressing TRBV2 and cultured in the presence of 2 μM NY-ESO-1116 and irradiated CD4– cells as feeders. As a control the CD4+ fraction depleted of TRBV2+ cells was cultured in the same manner. After 2 weeks, NY-ESO-1–reactive CD4+ T cells were stained with DR4/NY-ESO-1116 tetramer and sorted by flow cytometry for isolation of the TCR chains. One of 2 similar in vitro cultures is shown. Cells were gated on lymphocytes, live cells, CD3+ cells, and CD4+ and CD8– cells. (B) Human CD4+ T cells were transduced with the NY-ESO-1–reactive TCRs, which were identified by combinatorial expression (Supplemental Figure 2) and stained with DR4/NY-ESO-1116 tetramer and for mTCRβ. The results are representative of 2 independent experiments. α and β sequences of NY-ESO-1–reactive TCRs are listed in Table 2. The untransduced sample is the same as that shown in Figure 1D, since experiments in Figure 1D and 2B were performed in parallel. Plotted cells were gated on lymphocytes, live cells, and CD3+ and CD4+ cells.