PMC

Overview of mechanisms and potential therapeutic targets as a strategy to improve tumor-antigen reactive T lymphocytes. These include a large variety of receptors (e.g., engineered TCRs, activating/inhibitory surface receptors, cytokine receptor) as well as TCR-downstream signaling molecules (e.g., SHP-1, SHP-2, PP2A) that regulate T cell activation, signaling, and function (e.g., killing, cytokine secretion) against cancer antigens. Of note, the scTv single VαVβ chain TCRs may be linked to intracellular signaling domains such as Lck and CD28, independently of the CD3 subunits (Aggen et al., ).

Model integrating the relationship between T cell responsiveness (e.g., cell signaling, gene expression, and functionality) and TCR-affinity (in K_D, μM) of human CD8 T lymphocytes engineered with anti-tumor TCR variants of optimized affinities (Irving et al., ; Hebeisen et al., ; Zhong et al., ). Optimal/maximal T cell effectiveness is observed with cells expressing affinities in the upper natural limit (K_D from 5 to 1 μM; dark green). Negative regulation mechanisms may counteract T cell responsiveness in T cells bearing very high affinities (depicted as blue gradients) (Corse et al., ; Slansky and Jordan, ; Hebeisen et al., ). Moreover, Zhong et al. () recently described an affinity threshold (K_D around 10 μM) for maximal anti-tumor activity and autoreactivity (depicted as orange gradients).