TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 22, 2021
- Source ID
- 10.1084/jem.20201966
Entities
People
- Andrea Schietinger
- Benjamin M. Whitlock
- Daniel K. Wells
- Doron Betel
- Emmanuel M. Bruno
- Fella Tamzalit
- Francisco J Sánchez-Rivera
- Friederike Dündar
- Gabriel Espinosa-Carrasco
- Laura Menocal
- Mary Philip
- Matthew D Hellmann
- Mojdeh Shakiba
- Morgan Huse
- Nadine A. Defranoux
- Nicholas D Socci
- Paul Zumbo
- Richard Koche
- Sandra Carson
- Scott W. Lowe
- Steven Camara
- Vincent Reuter
Organizations
- Cancer Research Institute
- Cornell University
- Damon Runyon Cancer Research Foundation
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- National Institutes of Health
- Parker Institute for Cancer Immunotherapy
- Pershing Square Foundation
- United States Department of Defense
- V Foundation for Cancer Research
- Vanderbilt University
- Weill Cornell Medicine