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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.
Introduction
The adoptive transfer of T cell receptor-engineered (TCR-engineered) tumor-reactive T cells is a promising approach to treat solid tumors. One crucial factor for successful therapy is the affinity of the therapeutic TCR to its cognate peptide-MHC molecule on the tumor. However, isolating highly functional TCRs against shared (self) tumor antigens can be difficult because tolerance mechanisms during T cell development may lead to their deletion in the host if the antigen is expressed in the thymus (1, 2). To overcome this limitation, we generated a mouse model in which T cells rearrange a diverse human TCR repertoire but because the mice lack human tumor antigens, they are not subject to the mechanisms of tolerance to such antigens (3, 4). Isolated HLA-A·02:01-restricted (HLA-A2-restricted) TCRs from this mouse model against tumor antigens MAGE-A1 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) showed higher functional activity compared with TCRs against the same epitopes from the human repertoire (3). Hence, we defined an optimal-affinity TCR operationally as a...