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 & Sheila A. Stewart

Nat Commun. 2016 Jun 8;7:11762.

Speaker: Wan-Yu Lee (李婉瑜)                                    Time: 15:00~16:00, Apr. 12th, 2017

Commentator: Dr. Bei-Chang Yang (楊倍昌老師)      Place: Room 601

Abstract:

Age is an important risk factor for developing a variety of cancers¹. The factors influence the increase of age-related cancers have been implied to the random mutations of incipient tumor cells and stromal changes. Although many gene mutations contributed to cancer have been known, the mechanisms of how the stromal regions drive the cellular transformation remain uncertain. Inflammatory responses include increase in cytokines production by immune cells seem to serve as a link between stromal compartment changes and tumor development². Some studies have indicated that the accumulation of senescent cells during aging may contribute to increase of inflammation. Indeed, reduced tumorigenesis occurs when senescence cells are depleted in mice. However, how senescence bring about tumorigenesis remains to be clarified. Here, the authors develop a mouse model that mimics the aged skin microenvironment to determine whether senescence stromal cells drives tumorigenesis. By using this model, they first found that the senescent stromal cells can drive increased inflammation and localized immunosuppressive cells near to stromal cells. They then, identified these immunosuppressive cells, as granulocytic myeloid derived suppressor cells (G-MDSCs) suppress CD8+ T cell function and promote tumor growth. Next, they manifested that the main stromal-derived senescence-associated secretory phenotype factor IL-6 is necessary to drive G-MDSCs accumulation and tumor promotion. Consistent with the findings in mouse model, they also found increase of immune cells localized near senescent stromal cells in aged and cancer free human skin. Taken together these data, suggest that the accumulation of senescent stromal cells create an immunosuppressive microenvironment which can shelter the incipient tumor cells from effective anti-tumor immune responses, thus allowing them to proliferate and progress. These findings provide the possibility of senescent cells as an important preventative target.

References:

1.     DePinho, R. A. The age of cancer. Nature. 2000 Nov 9;408(6809):248-54.

2.     Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009 Apr 15;182(8):4499-506.