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

TitleTOX is a critical regulator of tumour-specific T cell differentiation.
Publication TypeJournal Article
Year of Publication2019
AuthorsScott AC, D√ľndar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, Trivedi P, Menocal L, Appleby H, Camara S, Zamarin D, Walther T, Snyder A, Femia MR, Comen EA, Wen HY, Hellmann MD, Anandasabapathy N, Liu Y, Altorki NK, Lauer P, Levy O, Glickman MS, Kaye J, Betel D, Philip M, Schietinger A
JournalNature
Volume571
Issue7764
Pagination270-274
Date Published2019 07
ISSN1476-4687
KeywordsAnimals, CD8-Positive T-Lymphocytes, Cell Differentiation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, High Mobility Group Proteins, Homeodomain Proteins, Humans, Immunologic Memory, Lymphocytes, Tumor-Infiltrating, Mice, Neoplasms, Phenotype, Receptors, Antigen, T-Cell, Transcription, Genetic
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.

DOI10.1038/s41586-019-1324-y
Alternate JournalNature
PubMed ID31207604
PubMed Central IDPMC7698992
Grant ListR01 AI054977 / AI / NIAID NIH HHS / United States
P30 DK058404 / DK / NIDDK NIH HHS / United States
K08 CA158069 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R00 CA172371 / CA / NCI NIH HHS / United States
U54 CA209975 / CA / NCI NIH HHS / United States
DP2 CA225212 / CA / NCI NIH HHS / United States