Analysis of T cell receptor signal strength, and its manipulation, can provide powerful metrics for monitoring outcomes to immunotherapy
June 28, 2022
Abstract
How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice, we characterized early quantitative and qualitative changes that occur in CD4+ T cells in relation to TCR signaling strength. We captured how dose- and time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates T cell activation thresholds and visualized the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 immunotherapy leads to an increased TCR signal strength. We defined a strong TCR signal metric of five genes upregulated by anti-PD1 in T cells (TCR.strong), which was superior to a canonical T cell activation gene signature in stratifying melanoma patient outcomes to anti-PD1 therapy. Our study therefore reveals how analysis of TCR signal strength—and its manipulation—can provide powerful metrics for monitoring outcomes to immunotherapy.
Source:
Elliot, T. A. E., Jennings, E. K., Lecky, D. A. J., Thawait, N., Flores-Langarica, A., Copland, A., Maslowski, K. M., Wraith, D. C., & Bending, D. (2021). Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength. Immunity, 54(11). https://doi.org/10.1016/j.immu...