Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis

• Published in: Nature communications Vol. 7; no. 1; p. 11762
• Main Authors: Ruhland, Megan K., Loza, Andrew J., Capietto, Aude-Helene, Luo, Xianmin, Knolhoff, Brett L., Flanagan, Kevin C., Belt, Brian A., Alspach, Elise, Leahy, Kathleen, Luo, Jingqin, Schaffer, Andras, Edwards, John R., Longmore, Gregory, Faccio, Roberta, DeNardo, David G., Stewart, Sheila A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-06-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/44; 13/51; 13/89; 14/1; 14/35; 38/1; 631/250/251/1574; 631/67/327; 631/67/395; 631/80/509; 64/60; Adult; Age; Animals; Antigens, Ly - metabolism; Bone surgery; Cancer; Carcinogenesis - metabolism; Carcinogenesis - pathology; CD11b Antigen - metabolism; Cell cycle; Cell Line; Cell Proliferation; Cellular Senescence; Cytokines; Fibroblasts - pathology; Humanities and Social Sciences; Humans; Immune system; Immunologic Surveillance; Immunosuppression; Inflammation - pathology; Interleukin-6 - metabolism; Medicine; Mice; Middle Aged; multidisciplinary; Mutation; Myeloid-Derived Suppressor Cells - pathology; Science; Science (multidisciplinary); Senescence; Skin - pathology; Stromal Cells - pathology; T-Lymphocytes, Regulatory - metabolism; Tumor Microenvironment; Tumorigenesis; United States > US; Missouri
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11762

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.
The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.