TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma

Wang, X; He, Qifeng; Shen, Haiyuan; Xia, Anliang; Tian, Wen‐de; Yu, Weiwei; Sun, Beicheng

doi:10.1016/j.jhep.2019.05.015

Cited by 213 publications

(182 citation statements)

References 34 publications

Supporting

Mentioning

176

Contrasting

Order By: Relevance

“…One explanation for the limited efficacy of PD-1/PD-L1 blockade relates to its inability to reverse the exhaustion-associated epigenetic imprint (Pauken et al, 2016). Recent studies have identified TOX, TOX2, and AP-1 family members as central regulators of human T cell exhaustion that promote widespread transcriptional and epigenetic dysregulation (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Seo et al, 2019;Wang et al, 2019;Yao et al, 2019). These findings have enabled new approaches to mitigate exhaustion, including enforced expression of c-Jun or CRISPR-mediated deletion of TOX, TOX2, or NR4A family TFs (Chen et al, 2019a;Seo et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Weber

Lynn

Parker

et al. 2020

Preprint

View full text Add to dashboard Cite

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to CAR-T cell therapeutics. Using a model wherein tonic CAR signaling induces hallmark features of exhaustion, we employed a drug-regulatable CAR to test the impact of transient cessation of receptor signaling (i.e. "rest") on the development and maintenance of exhaustion. Induction of rest in exhausting or already-exhausted CAR-T cells resulted in acquisition of a memory-like phenotype, improved antitumor functionality, and wholescale transcriptional and epigenetic reprogramming. Similar results were achieved with the Src kinase inhibitor dasatinib, which reversibly suppresses CAR signaling. The degree of functional reinvigoration was proportional to the duration of rest and was associated with expression of transcription factors TCF1 and LEF1. This work demonstrates that transient cessation of CAR-T cell signaling can enhance anti-tumor potency by preventing or reversing exhaustion and challenges the paradigm that exhaustion is an epigenetically fixed state.

show abstract

Section: Discussionmentioning

confidence: 99%

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Weber

Lynn

Parker

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The underlying mechanism involves a TOX-induced decrease in PD-1 degradation and promotion of PD-1 endocytic recycling to the cell surface. Knocking down TOX in tumor-specific CD8 + T cells promoted the anti-tumor effects of these T cells, exhibiting the synergetic role of anti-PD-1therapy (Wang et al, 2019d).…”

Section: Quigley Et Al 2010mentioning

confidence: 97%

“…Liu X. et al, 2019 TOX High-mobility group (HMG)-box transcription factor that regulates the progression of T cell dysfunction and the maintenance of exhausted T cells. Alfei et al, 2019;Wang et al, 2019d TCF-1 Transcriptional factor that supports stem-cell function of PD-1 + TILs and the formation of exhausted T cell progenitors, which are described that express TCF1 and intermediate amounts of PD-1 (PD-1 int ). Chen Z. et al, 2019 Eomes Transcriptional factor that correlates with T cell exhaustion by inducing co-inhibitory molecule B7 superfamily member 1(B7S1) pathway.…”

Section: Nr4amentioning

confidence: 99%

T Cell Dysfunction and Exhaustion in Cancer

Zhang

et al. 2020

Front. Cell Dev. Biol.

257

209

View full text Add to dashboard Cite

Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.

show abstract

“…Recently, TOX protein was found to regulate the expression of multiple inhibitory molecules including PD‐1, Lag‐3, and Tim‐3, and determine the survival of dysfunctional/exhausted T cells using scRNA‐seq . Three other groups also independently confirmed the findings …”

Section: Application Of Scrna‐seq In Immunologymentioning

confidence: 78%

“…74 Three other groups also independently confirmed the findings. [75][76][77] As for cancer, metallothionein 1 (MT1) was identified as the topranking gene in dysfunctional CD8 + T cells using SMART2-seq. 78 The subsequent study further reported a transitional population that gives rise to dysfunctional CD8 + T cells with highly similar transcriptional signature among different human cancer.…”

Section: Application Of Scrna-seq In Cancer Infectious and Autoimmumentioning

confidence: 99%

Dissecting the human immune system with single cell RNA sequencing technology

Liu

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Single‐cell RNA sequencing (scRNA‐seq) is a powerful new technology allowing the analysis of transcriptomes from individual cell and is ideally suited to dissect immune cell heterogeneity. ScRNA‐seq has already been applied to identify novel immune cell subsets, elaborate cellular differentiation trajectories, and elucidate immunopathogenic mechanisms. Here, we briefly discuss the recent progresses and challenges in the scRNA‐seq technology including the workflow, recent applications in immunology, and potential hurdles that need to be overcome. This review will highlight how single cell technology promotes our understanding of human immunology.

show abstract

TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma

Cited by 213 publications

References 34 publications

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

T Cell Dysfunction and Exhaustion in Cancer

Dissecting the human immune system with single cell RNA sequencing technology

Contact Info

Product

Resources

About