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

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, Koche, Richard P, Reuter, Vincent P, Socci, Nicholas D, Whitlock, Benjamin, Tamzalit, Fella, Huse, Morgan, Hellmann, Matthew D, Wells, Daniel K, Defranoux, Nadine A, Betel, Doron, Philip, Mary, Schietinger, Andrea (February 2022) TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. Journal of Experimental Medicine, 219 (2). ISSN 0022-1007

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URL: https://www.ncbi.nlm.nih.gov/pubmed/34935874
DOI: 10.1084/jem.20201966

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.

Item Type: Paper
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
CSHL Authors:
Communities: CSHL labs > Lowe lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 7 February 2022
Date Deposited: 14 Jan 2022 19:32
Last Modified: 14 Jan 2022 19:32
PMCID: PMC8704919
URI: https://repository.cshl.edu/id/eprint/40480

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