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 Edwards, Gregory Longmore, Roberta Faccio, David DeNardo, Sheila A. Stewart

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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.

Original languageEnglish
Article number11762
JournalNature communications
Volume7
DOIs
StatePublished - Jun 8 2016

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    Ruhland, M. K., Loza, A. J., Capietto, A. H., Luo, X., Knolhoff, B. L., Flanagan, K. C., Belt, B. A., Alspach, E., Leahy, K., Luo, J., Schaffer, A., Edwards, J., Longmore, G., Faccio, R., DeNardo, D., & Stewart, S. A. (2016). Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nature communications, 7, [11762]. https://doi.org/10.1038/ncomms11762