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

Author

Listed:
  • Andrew C. Scott

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences)

  • Friederike Dündar

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Paul Zumbo

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Smita S. Chandran

    (Parker Institute for Cancer Immunotherapy
    Memorial Sloan Kettering Cancer Center)

  • Christopher A. Klebanoff

    (Parker Institute for Cancer Immunotherapy
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Mojdeh Shakiba

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Prerak Trivedi

    (Memorial Sloan Kettering Cancer Center)

  • Laura Menocal

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences)

  • Heather Appleby

    (Memorial Sloan Kettering Cancer Center)

  • Steven Camara

    (Memorial Sloan Kettering Cancer Center)

  • Dmitriy Zamarin

    (Parker Institute for Cancer Immunotherapy
    Memorial Sloan Kettering Cancer Center)

  • Tyler Walther

    (Memorial Sloan Kettering Cancer Center)

  • Alexandra Snyder

    (Memorial Sloan Kettering Cancer Center)

  • Matthew R. Femia

    (Parker Institute for Cancer Immunotherapy
    Memorial Sloan Kettering Cancer Center)

  • Elizabeth A. Comen

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Hannah Y. Wen

    (Memorial Sloan Kettering Cancer Center)

  • Matthew D. Hellmann

    (Parker Institute for Cancer Immunotherapy
    Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College)

  • Niroshana Anandasabapathy

    (Weill Cornell Graduate School of Medical Sciences
    Weill Cornell Medical College)

  • Yong Liu

    (Weill Cornell Medical College)

  • Nasser K. Altorki

    (New York Presbyterian Hospital)

  • Peter Lauer

    (Aduro Biotech, Inc.)

  • Olivier Levy

    (Memorial Sloan Kettering Cancer Center)

  • Michael S. Glickman

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences)

  • Jonathan Kaye

    (Cedars-Sinai Medical Center)

  • Doron Betel

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Mary Philip

    (Memorial Sloan Kettering Cancer Center
    Vanderbilt University Medical Center)

  • Andrea Schietinger

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences
    Parker Institute for Cancer Immunotherapy)

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.

Suggested Citation

  • Andrew C. Scott & Friederike Dündar & Paul Zumbo & Smita S. Chandran & Christopher A. Klebanoff & Mojdeh Shakiba & Prerak Trivedi & Laura Menocal & Heather Appleby & Steven Camara & Dmitriy Zamarin & , 2019. "TOX is a critical regulator of tumour-specific T cell differentiation," Nature, Nature, vol. 571(7764), pages 270-274, July.
  • Handle: RePEc:nat:nature:v:571:y:2019:i:7764:d:10.1038_s41586-019-1324-y
    DOI: 10.1038/s41586-019-1324-y
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    Cited by:

    1. Alexandria C. Wells & Kaito A. Hioki & Constance C. Angelou & Adam C. Lynch & Xueting Liang & Daniel J. Ryan & Iris Thesmar & Saule Zhanybekova & Saulius Zuklys & Jacob Ullom & Agnes Cheong & Jesse Ma, 2023. "Let-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Marcel P. Trefny & Nicole Kirchhammer & Priska Auf der Maur & Marina Natoli & Dominic Schmid & Markus Germann & Laura Fernandez Rodriguez & Petra Herzig & Jonas Lötscher & Maryam Akrami & Jane C. Stin, 2023. "Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Kateryna Onyshchenko & Ren Luo & Elena Guffart & Simone Gaedicke & Anca-Ligia Grosu & Elke Firat & Gabriele Niedermann, 2023. "Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Kenro Tanoue & Hirofumi Ohmura & Koki Uehara & Mamoru Ito & Kyoko Yamaguchi & Kenji Tsuchihashi & Yudai Shinohara & Peng Lu & Shingo Tamura & Hozumi Shimokawa & Taichi Isobe & Hiroshi Ariyama & Yoshih, 2024. "Spatial dynamics of CD39+CD8+ exhausted T cell reveal tertiary lymphoid structures-mediated response to PD-1 blockade in esophageal cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Solhwi Lee & Kunhee Lee & Hyeonjin Bae & Kyungmin Lee & Junghwa Lee & Junhui Ma & Ye Ji Lee & Bo Ryeong Lee & Woong-Yang Park & Se Jin Im, 2023. "Defining a TCF1-expressing progenitor allogeneic CD8+ T cell subset in acute graft-versus-host disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Markus Haake & Beatrice Haack & Tina Schäfer & Patrick N. Harter & Greta Mattavelli & Patrick Eiring & Neha Vashist & Florian Wedekink & Sabrina Genssler & Birgitt Fischer & Julia Dahlhoff & Fatemeh M, 2023. "Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. Sandra Tietscher & Johanna Wagner & Tobias Anzeneder & Claus Langwieder & Martin Rees & Bettina Sobottka & Natalie Souza & Bernd Bodenmiller, 2023. "A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    8. Hussein A. Abbas & Dapeng Hao & Katarzyna Tomczak & Praveen Barrodia & Jin Seon Im & Patrick K. Reville & Zoe Alaniz & Wei Wang & Ruiping Wang & Feng Wang & Gheath Al-Atrash & Koichi Takahashi & Jing , 2021. "Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    9. Hideki Ogura & Jin Gohda & Xiuyuan Lu & Mizuki Yamamoto & Yoshio Takesue & Aoi Son & Sadayuki Doi & Kazuyuki Matsushita & Fumitaka Isobe & Yoshihiro Fukuda & Tai-Ping Huang & Takamasa Ueno & Naomi Mam, 2022. "Dysfunctional Sars-CoV-2-M protein-specific cytotoxic T lymphocytes in patients recovering from severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Rui Sun & Chao Lei & Zhishan Xu & Xuemei Gu & Liu Huang & Liang Chen & Yi Tan & Min Peng & Kavitha Yaddanapudi & Leah Siskind & Maiying Kong & Robert Mitchell & Jun Yan & Zhongbin Deng, 2024. "Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    11. Kai Markus Schneider & Antje Mohs & Wenfang Gui & Eric J. C. Galvez & Lena Susanna Candels & Lisa Hoenicke & Uthayakumar Muthukumarasamy & Christian H. Holland & Carsten Elfers & Konrad Kilic & Caroli, 2022. "Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Feng Xie & Xiaoxue Zhou & Peng Su & Heyu Li & Yifei Tu & Jinjin Du & Chen Pan & Xiang Wei & Min Zheng & Ke Jin & Liyan Miao & Chao Wang & Xuli Meng & Hans Dam & Peter Dijke & Long Zhang & Fangfang Zho, 2022. "Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    13. Victoria Stary & Ram V. Pandey & Julia List & Lisa Kleissl & Florian Deckert & Julijan Kabiljo & Johannes Laengle & Vasileios Gerakopoulos & Rudolf Oehler & Lukas Watzke & Matthias Farlik & Samuel W. , 2024. "Dysfunctional tumor-infiltrating Vδ1 + T lymphocytes in microsatellite-stable colorectal cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    15. Yi Liu & Brian Debo & Mingfeng Li & Zhennan Shi & Wanqiang Sheng & Yang Shi, 2021. "LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    16. Leticia Laura Niborski & Paul Gueguen & Mengliang Ye & Allan Thiolat & Rodrigo Nalio Ramos & Pamela Caudana & Jordan Denizeau & Ludovic Colombeau & Raphaël Rodriguez & Christel Goudot & Jean-Michel Lu, 2022. "CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    17. Sonali Jindal & Nathan D. Pennock & Duanchen Sun & Wesley Horton & Michelle K. Ozaki & Jayasri Narasimhan & Alexandra Q. Bartlett & Sheila Weinmann & Paul E. Goss & Virginia F. Borges & Zheng Xia & Pe, 2021. "Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    18. Meng-Han Wu & Felipe Valenca-Pereira & Francesca Cendali & Emily L. Giddings & Catherine Pham-Danis & Michael C. Yarnell & Amanda J. Novak & Tonya M. Brunetti & Scott B. Thompson & Jorge Henao-Mejia &, 2024. "Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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