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Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis

Author

Listed:
  • Jonathan W. Lo

    (Imperial College London)

  • Domenico Cozzetto

    (Imperial College London)

  • James L. Alexander

    (Imperial College London)

  • Nathan P. Danckert

    (Imperial College London)

  • Matthew Madgwick

    (Organisms and Ecosystems, Earlham Institute
    Quadram Institute Bioscience)

  • Naomi Knox

    (Imperial College London)

  • Jillian Yong Xin Sieh

    (King’s College London)

  • Marton Olbei

    (Imperial College London
    Organisms and Ecosystems, Earlham Institute
    Quadram Institute Bioscience)

  • Zhigang Liu

    (Imperial College London)

  • Hajir Ibraheim

    (Imperial College London)

  • Jesus Miguens Blanco

    (Imperial College London)

  • Hiromi Kudo

    (Imperial College London)

  • Rocio Castro Seoane

    (Imperial College London)

  • Lucia A. Possamai

    (Imperial College London)

  • Robert Goldin

    (Imperial College London)

  • Julian Marchesi

    (Imperial College London)

  • Tamas Korcsmaros

    (Imperial College London
    Organisms and Ecosystems, Earlham Institute
    Quadram Institute Bioscience)

  • Graham M. Lord

    (King’s College London
    University of Manchester)

  • Nick Powell

    (Imperial College London)

Abstract

Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.

Suggested Citation

  • Jonathan W. Lo & Domenico Cozzetto & James L. Alexander & Nathan P. Danckert & Matthew Madgwick & Naomi Knox & Jillian Yong Xin Sieh & Marton Olbei & Zhigang Liu & Hajir Ibraheim & Jesus Miguens Blanc, 2023. "Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41798-2
    DOI: 10.1038/s41467-023-41798-2
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    References listed on IDEAS

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