Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis

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. Edwards, Gregory Longmore, Roberta Faccio, David G. DeNardo and Sheila A. Stewart ()
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Megan K. Ruhland: Department of Cell Biology and Physiology
Andrew J. Loza: Department of Medicine
Aude-Helene Capietto: Department of Orthopedic Surgery
Xianmin Luo: Department of Cell Biology and Physiology
Brett L. Knolhoff: Department of Medicine
Kevin C. Flanagan: Department of Cell Biology and Physiology
Brian A. Belt: Department of Surgery
Elise Alspach: Department of Pathology and Immunology
Kathleen Leahy: Department of Cell Biology and Physiology
Jingqin Luo: Division of Biostatistics
Andras Schaffer: Department of Pathology and Immunology
John R. Edwards: Department of Medicine
Gregory Longmore: Department of Medicine
Roberta Faccio: Department of Orthopedic Surgery
David G. DeNardo: Department of Medicine
Sheila A. Stewart: Department of Cell Biology and Physiology

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11762

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