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Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death

Author

Listed:
  • K. Hayashi

    (Cedars-Sinai Medical Center
    Baylor College of Medicine)

  • F. Nikolos

    (Cedars-Sinai Medical Center)

  • Y. C. Lee

    (Taipei Medical University)

  • A. Jain

    (Baylor College of Medicine)

  • E. Tsouko

    (Baylor College of Medicine)

  • H. Gao

    (Cedars-Sinai Medical Center)

  • A. Kasabyan

    (Cedars-Sinai Medical Center)

  • H. E. Leung

    (Baylor College of Medicine)

  • A. Osipov

    (Cedars-Sinai Medical Center)

  • S. Y. Jung

    (Baylor College of Medicine)

  • A. V. Kurtova

    (Baylor College of Medicine)

  • K. S. Chan

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

Abstract

Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.

Suggested Citation

  • K. Hayashi & F. Nikolos & Y. C. Lee & A. Jain & E. Tsouko & H. Gao & A. Kasabyan & H. E. Leung & A. Osipov & S. Y. Jung & A. V. Kurtova & K. S. Chan, 2020. "Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19970-9
    DOI: 10.1038/s41467-020-19970-9
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    Cited by:

    1. Xuan Wang & Yingqi Liu & Chencheng Xue & Yan Hu & Yuanyuan Zhao & Kaiyong Cai & Menghuan Li & Zhong Luo, 2022. "A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Charlotte R. Bell & Victoria S. Pelly & Agrin Moeini & Shih-Chieh Chiang & Eimear Flanagan & Christian P. Bromley & Christopher Clark & Charles H. Earnshaw & Maria A. Koufaki & Eduardo Bonavita & Sant, 2022. "Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Huiling Zhou & Dongsheng Tang & Yingjie Yu & Lingpu Zhang & Bin Wang & Johannes Karges & Haihua Xiao, 2023. "Theranostic imaging and multimodal photodynamic therapy and immunotherapy using the mTOR signaling pathway," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Fotis Nikolos & Kazukuni Hayashi & Xen Ping Hoi & Mark Ellie Alonzo & Qianxing Mo & Armine Kasabyan & Hideki Furuya & Jane Trepel & Dolores Vizio & Jlenia Guarnerio & Dan Theodorescu & Charles Rosser , 2022. "Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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