TOX 是肿瘤特异性 T 细胞分化的关键调节因子,Nature

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TOX 是肿瘤特异性 T 细胞分化的关键调节因子
Nature ( IF 50.5 ) Pub Date : 2019-06-17 , DOI: 10.1038/s41586-019-1324-y
Andrew C Scott _{1,

2} , Friederike Dündar _{3,

4} , Paul Zumbo _{3,

4} , Smita S Chandran _{5,

6} , Christopher A Klebanoff _{5,

6,

7,

8} , Mojdeh Shakiba _{1,

3} , Prerak Trivedi ₁ , Laura Menocal _{1,

2} , Heather Appleby ₁ , Steven Camara ₁ , Dmitriy Zamarin _{5,

7} , Tyler Walther ₇ , Alexandra Snyder ₇ , Matthew R Femia _{5,

6} , Elizabeth A Comen _{7,

8} , Hannah Y Wen ₉ , Matthew D Hellmann _{5,

7,

8} , Niroshana Anandasabapathy _{2,

10} , Yong Liu ₁₀ , Nasser K Altorki ₁₁ , Peter Lauer ₁₂ , Olivier Levy ₁ , Michael S Glickman _{1,

2} , Jonathan Kaye ₁₃ , Doron Betel _{4,

14,

15} , Mary Philip _{1,

16} , Andrea Schietinger _{1,

2,

5}

Affiliation

Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
Parker Institute for Cancer Immunotherapy, New York, NY, USA.
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weill Cornell Medical College, New York, NY, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Dermatology, Weill Cornell Medical College, New York, NY, USA.
Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA.
Aduro Biotech, Inc., Berkeley, CA, USA.
Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.

肿瘤特异性 CD8 T 细胞功能障碍是一种分化状态，不同于功能效应或记忆 T 细胞状态 1-6。在这里，我们将核因子 TOX 确定为肿瘤特异性 T (TST) 细胞分化的关键调节因子。我们表明，TOX 在来自肿瘤的功能失调的 TST 细胞和慢性病毒感染期间耗尽的 T 细胞中高度表达。TOX 的表达由慢性 T 细胞受体刺激和 NFAT 激活驱动。体外效应 T 细胞中 TOX 的异位表达诱导了与 T 细胞衰竭相关的转录程序。相反，肿瘤中 TST 细胞中 Tox 的缺失消除了耗竭程序：Tox 缺失的 TST 细胞不会上调抑制性受体（如 Pdcd1、Entpd1、Havcr2、Cd244 和 Tigit）的基因，其染色质在很大程度上仍然难以接近，并保留了 TCF-1 等转录因子的高表达。尽管它们的免疫表型正常，“未耗尽”，但 Tox 缺失的 TST 细胞仍然功能失调，这表明抑制性受体表达的调节与效应器功能的丧失无关。值得注意的是，尽管 Tox 缺失的 CD8 T 细胞在应对急性感染时正常分化为效应和记忆状态，但 Tox 缺失的 TST 细胞未能在肿瘤中持续存在。我们假设在慢性抗原刺激（如癌症）的情况下，TOX 诱导的耗竭程序有助于防止 T 细胞过度刺激和活化诱导的细胞死亡。

"点击查看英文标题和摘要"

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

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. The nuclear factor TOX is highly expressed in antigen-specific dysfunctional T cells in tumours and exhausted T cells during chronic viral infection and is a crucial regulator of the differentiation of tumour-specific T cells.

更新日期：2019-06-17

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