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High-affinity T cell receptors for adoptive cell transfer
Ariel Isser, Jonathan P. Schneck
Ariel Isser, Jonathan P. Schneck
Published December 10, 2018
Citation Information: J Clin Invest. 2019;129(1):69-71. https://doi.org/10.1172/JCI125471.
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Commentary

High-affinity T cell receptors for adoptive cell transfer

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Abstract

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.

Authors

Ariel Isser, Jonathan P. Schneck

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Figure 1

Optimal-affinity CD4+ T cells for enhanced antitumor response.

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Optimal-affinity CD4+ T cells for enhanced antitumor response.
(A) Mouse...
(A) Mouse hosts with human TCR and HLA genes generate “optimal-affinity” TCRs. As opposed to human hosts — which display self-antigens in the thymus and delete T cells that bind self-MHC and self-peptide with high affinity in a process known as negative selection — mouse hosts that lack human peptides but have human TCRs and HLA molecules can generate TCRs that bind human MHC and human peptide with high affinity. These are so-called optimal-affinity TCRs. (B) The wide range of effector and helper roles of CD4+ T cells in the antitumor response. CD4+ T cells can directly lyse tumor cells that have constitutive or inducible MHC II expression. Additionally, they can indirectly lead to tumor cell lysis by recruiting and activating macrophages and NK cells, which can release tumor antigens that can be presented by professional antigen-presenting cells such as dendritic cells to CD8+ T cells. Finally, they can also license dendritic cells, enhancing the activation and memory formation of tumor-specific CD8+ T cells.
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