TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion
Name
jem_20201966.pdf
Description
Published version
Size
4.94 MB
Format
Adobe PDF
Checksum (MD5)
662dd008552fabf85e0dcb7ac9a8555c
Author(s)
Shakiba, Mojdeh
Zumbo, Paul
Espinosa-Carrasco, Gabriel
Menocal, Laura
Dündar, Friederike
Carson, Sandra E
Bruno, Emmanuel M
Sanchez-Rivera, Francisco J
Lowe, Scott W
Camara, Steven
Date Issued
February 7, 2022
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Mojdeh Shakiba, Paul Zumbo, Gabriel Espinosa-Carrasco, Laura Menocal, Friederike Dündar, Sandra E. Carson, Emmanuel M. Bruno, Francisco J. Sanchez-Rivera, Scott W. Lowe, Steven Camara, Richard P. Koche, Vincent P. Reuter, Nicholas D. Socci, Benjamin Whitlock, Fella Tamzalit, Morgan Huse, Matthew D. Hellmann, Daniel K. Wells, Nadine A. Defranoux, Doron Betel, Mary Philip, Andrea Schietinger; TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. J Exp Med 7 February 2022; 219 (2): e20201966.
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-Noncommercial-ShareAlike
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DOI of Published Version
https://doi.org/10.1084/jem.20201966
