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TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. | LitMetric

AI Article Synopsis

  • * High signal strength interactions lead to TST cell dysfunction and up-regulation of inhibitory receptors, while low signal strength allows TST cells to maintain some functionality, yet neither effectively controls tumors.
  • * Adjusting signal strength using CRISPR-Cas9 to an intermediate range enhances the TST cells' ability to fight tumors, highlighting the importance of TCR signal strength for improving T cell-based cancer therapies.

Article Abstract

T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9-mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell-based cancer immunotherapies.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704919PMC
http://dx.doi.org/10.1084/jem.20201966DOI Listing

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