Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy

Abstract

Oxygenation levels are a determinative factor in T cell function. Here we describe that the oxygen tensions sensed by mouse and human T cells at the moment of activation act to persistently modulate both differentiation and function. We found that in a protocol of CAR-T cell generation, 24 hours of low oxygen levels during initial CD8+ T cell priming is sufficient to enhance antitumour cytotoxicity in a preclinical model. This is the case even when CAR-T cells are subsequently cultured under high oxygen tensions prior to adoptive transfer. Increased hypoxia inducible transcription factor (HIF) expression was able to alter T cell fate in a similar manner to exposure to low oxygen tensions; however, only a controlled or temporary increase in HIF signalling was able to consistently improve cytotoxic function of T cells. These data show that oxygenation levels during and immediately after T cell activation play an essential role in regulating T cell function.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided

Article and author information

Author details

  1. Pedro P Cunha

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3814-6289
  2. Eleanor Minogue

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Lena CM Krause

    Institute of Cardiovascular Physiology, Georg-August University, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3375-2850
  4. Rita M Hess

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5547-4172
  5. David Bargiela

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Brennan J Wadsworth

    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9183-227X
  7. Laura Barbieri

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Carolin Brombach

    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  9. Iosifina P Foskolou

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Ivan Bogeski

    Institute of Cardiovascular Physiology, Georg-August University, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9879-7174
  11. Pedro Velica

    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  12. Randall S Johnson

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    rsj33@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4084-6639

Funding

Wellcome Trust (214283/Z/18/Z)

  • Randall S Johnson

Knut och Alice Wallenbergs Stiftelse (Scholar)

  • Randall S Johnson

Vetenskapsrådet (2019-01485)

  • Randall S Johnson

Cancerfonden (CAN2018/808)

  • Randall S Johnson

Barncancerfonden (PR2020-007)

  • Randall S Johnson

Fundação para a Ciência e a Tecnologia (SFRH/BD/115612/2016)

  • Pedro P Cunha

Canadian Institutes of Health Research (Postdoctoral Fellowship)

  • Brennan J Wadsworth

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations for ethical experimentation in conformance with Swedish and EU laws and regulations. All of the animals were handled according to approved institutional animal care and use committee protocols. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Ethical Review Board of Northern Stockholm (approval Dnr 19683-2021) and the Swedish Ministry of Agriculture. All surgery was performed under anesthesia, and every effort was made to minimize suffering.

Human subjects: This study was performed in strict accordance with the recommendations for ethical experimentation in conformance with Swedish and EU laws and regulations. All of the animals were handled according to approved institutional animal care and use committee protocols. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Ethical Review Board of Northern Stockholm and the Swedish Ministry of Agriculture. All surgery was performed under anesthesia, and every effort was made to minimize suffering.

Copyright

© 2023, Cunha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Pedro P Cunha
  2. Eleanor Minogue
  3. Lena CM Krause
  4. Rita M Hess
  5. David Bargiela
  6. Brennan J Wadsworth
  7. Laura Barbieri
  8. Carolin Brombach
  9. Iosifina P Foskolou
  10. Ivan Bogeski
  11. Pedro Velica
  12. Randall S Johnson
(2023)
Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy
eLife 12:e84280.
https://doi.org/10.7554/eLife.84280

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https://doi.org/10.7554/eLife.84280

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