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Date of Award
Doctor of Philosophy (PhD)
The risk for developing cancer increases with age. This well-established phenomenon is likely driven, in part, by age-related increases in stochastic, epithelial, genetic mutations. Cancer requires that numerous complementary mutations occur in a single incipient tumor cell. Consequently, it is not surprising that time is needed for mutations to accumulate and transformation to occur. In addition to changes within the epithelium, there is growing appreciation for the importance of the stromal compartment in tumorigenesis. In an established tumor microenvironment, cancer-associated fibroblasts (CAFs) can fuel tumor progression. Additionally, activated stromal cells such as myofibroblasts and senescent fibroblasts can greatly influence both the transformation process in vitro and the progression of tumor development in vivo. Previous work has focused on the ability of tumors to co-opt the microenvironment and thus drive progression. However, whether pro-tumorigenic stromal changes can occur independently of neoplasia remains an unanswered question.
Senescent stromal cells accumulate in tissues with age and influence transformation and tumor progression. The mechanisms by which a senescent stromal compartment drives tumorigenesis remain to be fully elucidated. While senescent cells secrete growth factors that directly promote tumor growth, whether senescent cells can function in a non-transformed tissue to create a pro-tumorigenic microenvironment remains largely unknown. Interestingly, senescent cells secrete elevated levels of cytokines and chemokines as part of their distinctive secretory profile. Whether the secretion of these factors impacts inflammation and tumor development in older individuals remains an important and unaddressed question.
The lack of immune-competent mouse models for investigating the specific impact of stromal senescence has made it difficult to interrogate the interplay between these cells and the immune response. My work directly investigates the consequences of stromal senescence on inflammation through the use of a novel mouse model. This unique model allows for both spatial and temporal control of the induction of senescence. Using this system, I identified a role for senescence in the establishment of an immunosuppressive microenvironment prior to the appearance of a neoplastic clone. I demonstrated that senescence-derived IL-6 drives immunosuppression by promoting myeloid-derived suppressor cell (MDSC) accumulation. Additionally, I determined that senescence-mediated, MDSC accumulation functions to promote tumor growth through CD8+ T cell suppression. Further, I showed that targeting MDSCs directly, or depleting senescence-secreted factor IL-6, could reverse the tumor-permissive changes in the stroma. My work highlights a previously unidentified role for senescent stromal cells in dictating pro-tumorigenic immune responses and suggests IL-6 may be a beneficial target for reducing immunosuppression in aged microenvironments.
Chair and Committee
David DeNardo, Roberta Faccio, Daniel Link, Robert Schreiber, Katherine Weilbaecher
Ruhland, Megan Kiel, "Senescent Fibroblasts Drive Tumorigenesis Through the Establishment of an Immunosuppressive Microenvironment" (2015). Arts & Sciences Electronic Theses and Dissertations. 680.
Available for download on Thursday, August 15, 2115