IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-021-27731-5.html
   My bibliography  Save this article

A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells

Author

Listed:
  • Rupesh S. Patel

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute
    Scripps Green Hospital)

  • Rodrigo Romero

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center)

  • Emma V. Watson

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Anthony C. Liang

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Megan Burger

    (Massachusetts Institute of Technology)

  • Peter M. K. Westcott

    (Massachusetts Institute of Technology)

  • Kim L. Mercer

    (Massachusetts Institute of Technology)

  • Roderick T. Bronson

    (Harvard Medical School)

  • Eric C. Wooten

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Arjun Bhutkar

    (Massachusetts Institute of Technology)

  • Tyler Jacks

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Stephen J. Elledge

    (Brigham and Women’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

Abstract

The GATA4 transcription factor acts as a master regulator of development of multiple tissues. GATA4 also acts in a distinct capacity to control a stress-inducible pro-inflammatory secretory program that is associated with senescence, a potent tumor suppression mechanism, but also operates in non-senescent contexts such as tumorigenesis. This secretory pathway is composed of chemokines, cytokines, growth factors, and proteases. Since GATA4 is deleted or epigenetically silenced in cancer, here we examine the role of GATA4 in tumorigenesis in mouse models through both loss-of-function and overexpression experiments. We find that GATA4 promotes non-cell autonomous tumor suppression in multiple model systems. Mechanistically, we show that Gata4-dependent tumor suppression requires cytotoxic CD8 T cells and partially requires the secreted chemokine CCL2. Analysis of transcriptome data in human tumors reveals reduced lymphocyte infiltration in GATA4-deficient tumors, consistent with our murine data. Notably, activation of the GATA4-dependent secretory program combined with an anti-PD-1 antibody robustly abrogates tumor growth in vivo.

Suggested Citation

  • Rupesh S. Patel & Rodrigo Romero & Emma V. Watson & Anthony C. Liang & Megan Burger & Peter M. K. Westcott & Kim L. Mercer & Roderick T. Bronson & Eric C. Wooten & Arjun Bhutkar & Tyler Jacks & Stephe, 2022. "A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27731-5
    DOI: 10.1038/s41467-021-27731-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27731-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27731-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Judith Campisi & Pankaj Kapahi & Gordon J. Lithgow & Simon Melov & John C. Newman & Eric Verdin, 2019. "From discoveries in ageing research to therapeutics for healthy ageing," Nature, Nature, vol. 571(7764), pages 183-192, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Scott, Andrew J., 2023. "The economics of longevity – An introduction," The Journal of the Economics of Ageing, Elsevier, vol. 24(C).
    2. Old, Jonathan & Scott, Andrew, 2023. "Healthy ageing trends in England between 2002 to 2018: Improving but slowing and unequal," Department of Economics, Working Paper Series qt759110mx, Department of Economics, Institute for Business and Economic Research, UC Berkeley.
    3. Jinjie Duan & Wenhui Dong & Guangyan Wang & Wenjing Xiu & Guangyin Pu & Jingwen Xu & Chenji Ye & Xu Zhang & Yi Zhu & Chunjiong Wang, 2023. "Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Zi Wang & Lina Zou & Yiyan Zhang & Mengnan Zhu & Shuxian Zhang & Di Wu & Jianfeng Lan & Xiao Zang & Qi Wang & Hanxin Zhang & Zixing Wu & Huanhu Zhu & Di Chen, 2023. "ACS-20/FATP4 mediates the anti-ageing effect of dietary restriction in C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Hina Kosakamoto & Fumiaki Obata & Junpei Kuraishi & Hide Aikawa & Rina Okada & Joshua N. Johnstone & Taro Onuma & Matthew D. W. Piper & Masayuki Miura, 2023. "Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Qing Zou & Yingsi Lai & Zhao-Rong Lun, 2023. "Exploring the Association between Oxygen Concentration and Life Expectancy in China: A Quantitative Analysis," IJERPH, MDPI, vol. 20(2), pages 1-13, January.
    7. Seoyeon Lee & Mohammad Naimul Islam & Kaveh Boostanpour & Dvir Aran & Guangchun Jin & Stephanie Christenson & Michael A. Matthay & Walter L. Eckalbar & Daryle J. DePianto & Joseph R. Arron & Liam Mage, 2021. "Molecular programs of fibrotic change in aging human lung," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    8. Damien S. E. Broekharst & Sjaak Bloem & Marije Blok & Mariët Raatgever & Nathascha Hanzen & Jasmien J. E. de Vette, 2023. "Determining the Appropriate Support for Older Adults with Different Levels of Vitality and Health-Related Quality of Life: An Explanatory Study," IJERPH, MDPI, vol. 20(11), pages 1-11, June.
    9. Xueqing Wang & Quanlong Jiang & Hongdao Zhang & Zhidong He & Yuanyuan Song & Yifan Chen & Na Tang & Yifei Zhou & Yiping Li & Adam Antebi & Ligang Wu & Jing-Dong J. Han & Yidong Shen, 2024. "Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. Naina Bhatia-Dey & Thomas Heinbockel, 2021. "The Olfactory System as Marker of Neurodegeneration in Aging, Neurological and Neuropsychiatric Disorders," IJERPH, MDPI, vol. 18(13), pages 1-15, June.
    11. Takayoshi Sasako & Toshihiro Umehara & Kotaro Soeda & Kazuma Kaneko & Miho Suzuki & Naoki Kobayashi & Yukiko Okazaki & Miwa Tamura-Nakano & Tomoki Chiba & Domenico Accili & C. Ronald Kahn & Tetsuo Nod, 2022. "Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Betz, Ulrich A.K. & Arora, Loukik & Assal, Reem A. & Azevedo, Hatylas & Baldwin, Jeremy & Becker, Michael S. & Bostock, Stefan & Cheng, Vinton & Egle, Tobias & Ferrari, Nicola & Schneider-Futschik, El, 2023. "Game changers in science and technology - now and beyond," Technological Forecasting and Social Change, Elsevier, vol. 193(C).
    13. Old, Jonathan & Scott, Andrew, 2023. "Healthy ageing trends in England between 2002 to 2018: Improving but slowing and unequal," The Journal of the Economics of Ageing, Elsevier, vol. 26(C).
    14. Cox, Lynne S., 2022. "Therapeutic approaches to treat and prevent age-related diseases through understanding the underlying biological drivers of ageing," The Journal of the Economics of Ageing, Elsevier, vol. 23(C).
    15. Jorge Navarro & Miguel Cañete & Francisco J. Olivera & Marta Gil-Lacruz & Ana Gil-Lacruz & Pedro C. Marijuán, 2022. "The Cost of Loneliness: Assessing the Social Relationships of the Elderly via an Abbreviated Sociotype Questionnaire for inside and outside the Clinic," IJERPH, MDPI, vol. 19(3), pages 1-15, January.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27731-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.