TOX is a critical regulator of tumour-specific T cell differentiation

Andrew C. Scott, Friederike Dündar, Paul Zumbo, Smita S. Chandran, Christopher A. Klebanoff, Mojdeh Shakiba, Prerak Trivedi, Laura Menocal, Heather Appleby, Steven Camara, Dmitriy Zamarin, Tyler Walther, Alexandra Snyder, Matthew R. Femia, Elizabeth A. Comen, Hannah Y. Wen, Matthew D. Hellmann, Niroshana Anandasabapathy, Yong Liu, Nasser K. Altorki, Peter Lauer, Olivier Levy, Michael S. Glickman, Jonathan Kaye, Doron Betel, Mary Philip () and Andrea Schietinger ()
Additional contact information
Andrew C. Scott: Memorial Sloan Kettering Cancer Center
Friederike Dündar: Weill Cornell Medicine
Paul Zumbo: Weill Cornell Medicine
Smita S. Chandran: Parker Institute for Cancer Immunotherapy
Christopher A. Klebanoff: Parker Institute for Cancer Immunotherapy
Mojdeh Shakiba: Memorial Sloan Kettering Cancer Center
Prerak Trivedi: Memorial Sloan Kettering Cancer Center
Laura Menocal: Memorial Sloan Kettering Cancer Center
Heather Appleby: Memorial Sloan Kettering Cancer Center
Steven Camara: Memorial Sloan Kettering Cancer Center
Dmitriy Zamarin: Parker Institute for Cancer Immunotherapy
Tyler Walther: Memorial Sloan Kettering Cancer Center
Alexandra Snyder: Memorial Sloan Kettering Cancer Center
Matthew R. Femia: Parker Institute for Cancer Immunotherapy
Elizabeth A. Comen: Memorial Sloan Kettering Cancer Center
Hannah Y. Wen: Memorial Sloan Kettering Cancer Center
Matthew D. Hellmann: Parker Institute for Cancer Immunotherapy
Niroshana Anandasabapathy: Weill Cornell Graduate School of Medical Sciences
Yong Liu: Weill Cornell Medical College
Nasser K. Altorki: New York Presbyterian Hospital
Peter Lauer: Aduro Biotech, Inc.
Olivier Levy: Memorial Sloan Kettering Cancer Center
Michael S. Glickman: Memorial Sloan Kettering Cancer Center
Jonathan Kaye: Cedars-Sinai Medical Center
Doron Betel: Weill Cornell Medicine
Mary Philip: Memorial Sloan Kettering Cancer Center
Andrea Schietinger: Memorial Sloan Kettering Cancer Center

Nature, 2019, vol. 571, issue 7764, 270-274

Abstract: Abstract Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1–6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (18)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1324-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:571:y:2019:i:7764:d:10.1038_s41586-019-1324-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1324-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().