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DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity

Author

Listed:
  • Claire Vanpouille-Box

    (Weill Cornell Medicine)

  • Amandine Alard

    (New York University School of Medicine
    Present address: Cancer Research Center of Toulouse (CRCT), INSERM UMR 1037-University Toulouse III Paul Sabatier, Tumor Biology Department, Toulouse 31062, France)

  • Molykutty J. Aryankalayil

    (Radiation Oncology Branch, Center for Cancer Research and Radiation Research Program, National Cancer Institute, NIH)

  • Yasmeen Sarfraz

    (Weill Cornell Medicine)

  • Julie M. Diamond

    (Weill Cornell Medicine)

  • Robert J. Schneider

    (New York University School of Medicine)

  • Giorgio Inghirami

    (Weill Cornell Medicine)

  • C. Norman Coleman

    (Radiation Oncology Branch, Center for Cancer Research and Radiation Research Program, National Cancer Institute, NIH)

  • Silvia C. Formenti

    (Weill Cornell Medicine)

  • Sandra Demaria

    (Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12–18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8+ T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.

Suggested Citation

  • Claire Vanpouille-Box & Amandine Alard & Molykutty J. Aryankalayil & Yasmeen Sarfraz & Julie M. Diamond & Robert J. Schneider & Giorgio Inghirami & C. Norman Coleman & Silvia C. Formenti & Sandra Dema, 2017. "DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15618
    DOI: 10.1038/ncomms15618
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    Cited by:

    1. Meghana Pagadala & Timothy J. Sears & Victoria H. Wu & Eva Pérez-Guijarro & Hyo Kim & Andrea Castro & James V. Talwar & Cristian Gonzalez-Colin & Steven Cao & Benjamin J. Schmiedel & Shervin Goudarzi , 2023. "Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Ying Zhang & Raghava N. Sriramaneni & Paul A. Clark & Justin C. Jagodinsky & Mingzhou Ye & Wonjong Jin & Yuyuan Wang & Amber Bates & Caroline P. Kerr & Trang Le & Raad Allawi & Xiuxiu Wang & Ruosen Xi, 2022. "Multifunctional nanoparticle potentiates the in situ vaccination effect of radiation therapy and enhances response to immune checkpoint blockade," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Wen Zhou & Desmond Richmond-Buccola & Qiannan Wang & Philip J. Kranzusch, 2022. "Structural basis of human TREX1 DNA degradation and autoimmune disease," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    4. Nasser K. Altorki & Zachary H. Walsh & Johannes C. Melms & Jeffery L. Port & Benjamin E. Lee & Abu Nasar & Cathy Spinelli & Lindsay Caprio & Meri Rogava & Patricia Ho & Paul J. Christos & Ashish Saxen, 2023. "Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Damien Maggiorani & Oanh Le & Véronique Lisi & Séverine Landais & Gaël Moquin-Beaudry & Vincent Philippe Lavallée & Hélène Decaluwe & Christian Beauséjour, 2024. "Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Dina V. Hingorani & Michael M. Allevato & Maria F. Camargo & Jacqueline Lesperance & Maryam A. Quraishi & Joseph Aguilera & Ida Franiak-Pietryga & Daniel J. Scanderbeg & Zhiyong Wang & Alfredo A. Moli, 2022. "Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Rana Falahat & Anders Berglund & Patricio Perez-Villarroel & Ryan M. Putney & Imene Hamaidi & Sungjune Kim & Shari Pilon-Thomas & Glen N. Barber & James J. Mulé, 2023. "Epigenetic state determines the in vivo efficacy of STING agonist therapy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Samuel D. Chauvin & Shoichiro Ando & Joe A. Holley & Atsushi Sugie & Fang R. Zhao & Subhajit Poddar & Rei Kato & Cathrine A. Miner & Yohei Nitta & Siddharth R. Krishnamurthy & Rie Saito & Yue Ning & Y, 2024. "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    9. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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