Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis.
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.
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Megan K
MK
Ruhland
Department of Medicine,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Andrew J
AJ
Loza
Department of Orthopedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Aude-Helene
0000-0002-6782-3867
AH
Capietto
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Xianmin
X
Luo
Department of Medicine,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Brett L
BL
Knolhoff
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Kevin C
KC
Flanagan
Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Brian A
BA
Belt
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Elise
E
Alspach
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Kathleen
K
Leahy
Division of Biostatistics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Jingqin
0000-0003-2759-3072
J
Luo
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Andras
A
Schaffer
Department of Medicine,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Center For Pharmacogenomics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
John R
JR
Edwards
Department of Medicine,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|ICCE Institute, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
Gregory
G
Longmore
Department of Orthopedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Roberta
R
Faccio
Department of Medicine,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|ICCE Institute, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
David G
DG
DeNardo
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Department of Medicine,Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.|ICCE Institute, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.
Sheila A
SA
Stewart
D000328:Adult; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007157:Immunologic Surveillance; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells / Q000473:pathology; D012867:Skin / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D059016:Tumor Microenvironment
D000950:Antigens, Ly; D039481:CD11b Antigen; D015850:Interleukin-6; C480309:Ly6G antigen, mouse