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Adoptive cell transfer (ACT) of engineered T cell receptors (TCRs) for cancer immunotherapy has evolved from simple gene transfer of isolated TCRs to various affinity enhancement techniques that overcome limitations imposed by central and peripheral tolerance on TCR affinity. In the current issue of the JCI, Poncette et al. used mice with human TCRαβ and HLA gene loci to discover CD4⁺ TCRs of optimal affinity for cancer testis antigen (CTA) NY-ESO-1. They combined this TCR with a previously discovered NY-ESO-1–specific CD8⁺ TCR in an ACT fibrosarcoma tumor model to demonstrate the importance of T cell help in mediating antitumor responses.