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Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis

Author

Listed:
  • Megan K. Ruhland

    (Department of Cell Biology and Physiology
    Washington University School of Medicine)

  • Andrew J. Loza

    (Department of Medicine
    Washington University School of Medicine)

  • Aude-Helene Capietto

    (Department of Orthopedic Surgery
    Washington University School of Medicine)

  • Xianmin Luo

    (Department of Cell Biology and Physiology
    Washington University School of Medicine)

  • Brett L. Knolhoff

    (Department of Medicine
    Washington University School of Medicine)

  • Kevin C. Flanagan

    (Department of Cell Biology and Physiology
    Washington University School of Medicine)

  • Brian A. Belt

    (Department of Surgery
    Washington University School of Medicine)

  • Elise Alspach

    (Department of Pathology and Immunology
    Washington University School of Medicine)

  • Kathleen Leahy

    (Department of Cell Biology and Physiology
    Washington University School of Medicine)

  • Jingqin Luo

    (Division of Biostatistics
    Washington University School of Medicine
    Siteman Cancer Center
    Washington University School of Medicine)

  • Andras Schaffer

    (Department of Pathology and Immunology
    Washington University School of Medicine)

  • John R. Edwards

    (Department of Medicine
    Washington University School of Medicine
    Center For Pharmacogenomics
    Washington University School of Medicine)

  • Gregory Longmore

    (Department of Medicine
    Washington University School of Medicine
    Siteman Cancer Center
    Washington University School of Medicine)

  • Roberta Faccio

    (Department of Orthopedic Surgery
    Washington University School of Medicine
    Siteman Cancer Center
    Washington University School of Medicine)

  • David G. DeNardo

    (Department of Medicine
    Washington University School of Medicine
    Department of Pathology and Immunology
    Washington University School of Medicine)

  • Sheila A. Stewart

    (Department of Cell Biology and Physiology
    Washington University School of Medicine
    Department of Medicine
    Washington University School of Medicine)

Abstract

Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.

Suggested Citation

  • Megan K. Ruhland & Andrew J. Loza & Aude-Helene Capietto & Xianmin Luo & Brett L. Knolhoff & Kevin C. Flanagan & Brian A. Belt & Elise Alspach & Kathleen Leahy & Jingqin Luo & Andras Schaffer & John R, 2016. "Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis," Nature Communications, Nature, vol. 7(1), pages 1-18, September.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11762
    DOI: 10.1038/ncomms11762
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    Cited by:

    1. Lea Monteran & Nour Ershaid & Hila Doron & Yael Zait & Ye’ela Scharff & Shahar Ben-Yosef & Camila Avivi & Iris Barshack & Amir Sonnenblick & Neta Erez, 2022. "Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Hugo Croizer & Rana Mhaidly & Yann Kieffer & Geraldine Gentric & Lounes Djerroudi & Renaud Leclere & Floriane Pelon & Catherine Robley & Mylene Bohec & Arnaud Meng & Didier Meseure & Emanuela Romano &, 2024. "Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    3. Rana Salam & Alexa Saliou & Franck Bielle & Mathilde Bertrand & Christophe Antoniewski & Catherine Carpentier & Agusti Alentorn & Laurent Capelle & Marc Sanson & Emmanuelle Huillard & Léa Bellenger & , 2023. "Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Monika Licaj & Rana Mhaidly & Yann Kieffer & Hugo Croizer & Claire Bonneau & Arnaud Meng & Lounes Djerroudi & Kevin Mujangi-Ebeka & Hocine R. Hocine & Brigitte Bourachot & Ilaria Magagna & Renaud Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    5. Benjamin Assouline & Rachel Kahn & Lutfi Hodali & Reba Condiotti & Yarden Engel & Ela Elyada & Tzlil Mordechai-Heyn & Jason R. Pitarresi & Dikla Atias & Eliana Steinberg & Tirza Bidany-Mizrahi & Esthe, 2024. "Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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