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

Scott, Andrew; Dündar, Friederike; Zumbo, Paul; Chandran, Smita S.; Klebanoff, Christopher A.; Shakiba, Mojdeh; Trivedi, Prerak; Menocal, Laura; Appleby, Heather; Camara, Steven; Zamarin, Dmitriy; Walther, Tyler; Snyder, Alexandra; Femia, Matthew R.; Comen, Elizabeth; Wen, Hannah Y.; Hellmann, Matthew D.; Anandasabapathy, Niroshana; Liu, Yong; Altorki, Nasser K.; Lauer, Peter; Levy, Olivier; Glickman, Michael S.; Kaye, Jonathan; Betel, Doron; Philip, Mary; Schietinger, Andrea

doi:10.1038/s41586-019-1324-y

Cited by 843 publications

(839 citation statements)

References 46 publications

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“…A likely explanation is that the EM-like compartment is enriched in non tumor-specific cells, as multiple studies have shown the presence of large numbers of "bystander" T cells in human tumors (Simoni et al, 2018;Scheper et al, 2019) Figure 6 D), which is essential to establish and maintain the epigenetic T cell exhaustion program enabling T cells to persist in the context of chronic antigenic stimulation (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Yao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Unsupervised clustering on the high-dimensional space revealed the presence of four robust CD8 TIL clusters with distinct transcriptomic profiles. Cluster 1 (C1) was defined by high expression of inhibitory receptors Pdcd1, Havcr2, Ctla4, Tigit and Lag3, exhaustion-related transcription factors such as Batf and Tox (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Yao et al, 2019) and high expression of cytotoxic molecules (e.g. Gzmb,Prf1,Fasl), compatible with an exhausted state (Figure 1 B,C).…”

Section: Single-cell Rna-seq Of Cd8 Tils Reveals the Presence Of Exhamentioning

confidence: 99%

“…RNA-seq data from adoptively transferred (in vitro activated) OT-1 cells infiltrating B16-OVA tumors (anti-PD1 vs control) were obtained from GEO GSE93014 (Mognol et al, 2017). Differential expression data from tumor-specific CD8 TILs (liver cancer) knockout for TOX (TOX-KO) vs wildtype were obtained from Supplementary Table 1 of (Scott et al, 2019).…”

Section: Gene Signature Analysismentioning

confidence: 99%

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Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

Carmona

Siddiqui

Bilous

et al. 2019

Preprint

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Recent studies have proposed that tumor-specific tumor-infiltrating CD8 + T lymphocytes (CD8 TIL) can be classified into two main groups: "exhausted" TILs, characterized by high expression of the inhibitory receptors PD-1 and TIM-3 and lack of transcription factor 1 (Tcf1); and "memory-like" TILs, with self-renewal capacity and co-expressing Tcf1 and PD-1. However, a comprehensive definition of the heterogeneity existing within both tumor-specific and total CD8 TILs has yet to be clearly established.To investigate this heterogeneity at the transcriptomic level, we performed paired single-cell RNA and TCR sequencing of CD8 T cells infiltrating B16 murine melanoma tumors, including cells of known tumor specificity. Unsupervised clustering and gene signature analysis revealed four distinct CD8 TIL states -exhausted, memory-like, naïve and effector memory-like (EM-like) -and predicted novel markers, including Ly6C for the EM-like cells, that were validated by flow cytometry. Tumor-specific PMEL T cells were predominantly found within the exhausted and memory-like states but also within the EM-like state. Further, TCR repertoire sequencing revealed a large clonal expansion of exhausted, memory-like and EM-like cells with partial clonal relatedness between them. Finally, meta-analyses of public bulk and single-cell RNAseq data suggested that anti-PD-1 treatment induces expansion of EM-like cells.Our reference map of the transcriptomic landscape of murine CD8 TILs will help interpreting future bulk and single-cell transcriptomic studies and may guide the analysis of CD8 TIL subpopulations in response to therapeutic interventions.2

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Section: Discussionmentioning

confidence: 99%

Section: Single-cell Rna-seq Of Cd8 Tils Reveals the Presence Of Exhamentioning

confidence: 99%

Section: Gene Signature Analysismentioning

confidence: 99%

See 1 more Smart Citation

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

Carmona

Siddiqui

Bilous

et al. 2019

Preprint

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“…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

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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.

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Single‐cell transcriptomics reveal the intratumoral landscape of infiltrated T‐cell subpopulations in oral squamous cell carcinoma

Chen

Yang

et al. 2021

Molecular Oncology

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Systematic analysis of tumor‐infiltrating lymphocytes is essential for the development of new cancer treatments and the prediction of clinical responses to immunotherapy. Immunomodulatory drugs are used for the treatment of oral squamous cell carcinoma (OSCC), depending on immune infiltration profiles of the tumor microenvironment. In this study, we isolated 11,866 single T cells from tumors and paired adjacent normal tissues of three patients with OSCC. Using single‐cell RNA sequencing, we identified 14 distinct T‐cell subpopulations within the tumors and 5 T‐cell subpopulations in the adjacent normal tissues and delineated their developmental trajectories. Exhausted CD8+ T cells and regulatory CD4+ T cells (CD4+ Tregs) were enriched in OSCC tumors, potentially linked to tumor immunosuppression. Programmed death protein 1 (PD‐1) and cytotoxic T lymphocyte‐associated protein 4 (CTLA4) were identified as marker genes in exhausted CD8+ T cells, whereas forkhead box P3 (FOXP3) and CTLA4 were identified as markers of CD4+ Tregs. Furthermore, our data revealed that thymocyte selection‐associated high‐mobility group box (TOX) may be a key regulator of T‐cell dysfunction in the OSCC microenvironment. Overexpression of TOX upregulated expression of genes related to T‐cell dysfunction. In vitro experiments demonstrated that cytotoxic activity and proliferation efficiency of CD8+ T cells overexpressing PD‐1 or TOX were reduced. Notable, the transcription factor PRDM1 was found to transactivate TOX expression via a binding motif in the TOX promoter. Our findings provide valuable insight into the functional states and heterogeneity of T‐cell populations in OSCC that could advance the development of novel therapeutic strategies.

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

Cited by 843 publications

References 46 publications

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

Dissecting the human immune system with single cell RNA sequencing technology

Single‐cell transcriptomics reveal the intratumoral landscape of infiltrated T‐cell subpopulations in oral squamous cell carcinoma

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