| Autor: |
Natasha Thawait, Emma K. Jennings, Adriana Flores-Langarica, David Bending, David A.J. Lecky, Thomas A.E. Elliot, David C. Wraith |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.03.02.431957 |
| Popis: |
SummaryHow 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 as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.Key PointsTCR signal strength-dependent programming of CD4+ T cells revealed over time in vivoInhibitory receptor expression is dynamic, TCR signal strength dependent, and rapidly re-calibrates T cell activation thresholdsPD1 but not Lag3 blockade leads to a unique and increased TCR signal strength signature (coined TCR.strong)TCR.strong metric stratifies melanoma patient survival in response to Nivolumab (anti-PD1) therapy |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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