TOX is a critical regulator of tumour-specific T cell differentiation
Menée à l'aide de cellules mononucléées du sang périphérique humain, d'échantillons tumoraux et de modèles murins, cette étude met en évidence le rôle du facteur nucléaire TOX dans la régulation de la différenciation des lymphocytes T spécifiques de tumeur
Tumor-specific CD8 T cell dysfunction is a differentiation state distinct from the functional effector or memory T cell states1–6. Here we identify the nuclear factor, Thymocyte selection-associated HMG box protein, TOX, as a critical regulator of tumor-specific T cell (TST) differentiation. We show that TOX is highly expressed in dysfunctional TST from tumors and in exhausted T cells in chronic viral infection. TOX expression is driven by chronic TCR stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, Tox deletion in TST in tumors abrogated the exhaustion program: Tox-deleted TST did not upregulate inhibitory receptors (e.g. Pdcd1, Entpd1, Havcr2, Cd244, Tigit), whose chromatin remained largely inaccessible, and retained high expression of transcription factors such as TCF1. Despite their normal, “non-exhausted” immunophenotype, Tox-deleted TST remained dysfunctional, revealing that the regulation of inhibitory receptor expression is uncoupled from the loss of effector function. Importantly, while Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST failed to persist in tumors. We hypothesize that the TOX-induced exhaustion program serves to prevent T cell overstimulation and activation-induced cell death in settings of chronic antigen stimulation such as cancer.
Nature , résumé, 2019