TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion Journal Article
| Authors: | Shakiba, M.; Zumbo, P.; Espinosa-Carrasco, G.; Menocal, L.; Dündar, F.; Carson, S. E.; Bruno, E. M.; Sanchez-Rivera, F. J.; Lowe, S. W.; Camara, S.; Koche, R. P.; Reuter, V. P.; Socci, N. D.; Whitlock, B.; Tamzalit, F.; Huse, M.; Hellmann, M. D.; Wells, D. K.; Defranoux, N. A.; Betel, D.; Philip, M.; Schietinger, A. |
| Article Title: | 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 dysfunctionassociated 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. © 2021 Shakiba et al. |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 219 |
| Issue: | 2 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2022-02-07 |
| Start Page: | e20201966 |
| Language: | English |
| DOI: | 10.1084/jem.20201966 |
| PUBMED: | 34935874 |
| PROVIDER: | scopus |
| PMCID: | PMC8704919 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
Altmetric
Citation Impact
MSK Authors
Related MSK Work