Role of Cellular Senescence in Angiotensin II Induced Oxidative Stress and Immune Checkpoint Inhibitor Efficacy in Cancer Treatment
As the natural process of aging occurs along with stresses and insults from the environment, cells in various organs and tissues of the body can undergo senescence, a phase of arrested growth and exit from the cell cycle that is established in order to prevent further propagation of damaged cells. Though cellular senescence is acutely beneficial for the organism, chronic accumulation of senescent cells can have negative effects on organ function and overall survival. In this thesis dissertation, I will provide a background on senescence in various aspects. I will discuss the types of cellular senescence and their inducers along with typical features of senescent cells. The relationship that senescent cells and their senescence-associated secretory phenotype (SASP) have with cell signaling pathways will be discussed. The role senescent cells play in the development and pathogenesis of cancer will also be discussed. In addition, how certain drugs can induce cellular senescence and how senescence can have an impact on the efficacy of drug treatments will be assessed. Lastly, in vivo models of cellular senescence will be highlighted for their potential and ongoing use in the understanding and targeting of senescence. Subsequently, I will describe findings from two projects where I studied the impact of senescence in an animal model, INK-ATTAC that allows for detection and reversal of senescence. The first project was identifying the contribution of tissues and cell types that undergo senescence in response to low dose chronic angiotensin II administration. I observed that oxidative stress from low dose chronic angiotensin II caused induction of senescence in kidney endothelia that was accompanied by a signature of endothelial damage. Quite strikingly, elimination of senescent cells prevented the senescence and damage-related pathway activation and endothelial damage signature. The second project was to assess the impact of host cell senescence on the efficacy of immune checkpoint inhibitor treatment of a syngeneic mouse model of triple negative breast cancer. I observed that resistance to treatment with immune checkpoint inhibitors was ameliorated by the elimination of host senescent cells and resulted in an altered composition of immune cell infiltration into the tumors. Further analyses will be done to elucidate the pathways and proteins involved in the crosstalk between senescence and immune checkpoint inhibitor resistance.
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Effects of CDK4/6 Inhibitor-Induced Stromal Senescence on the Metastatic Niche and Metastasis of Breast Cancer Gallanis, Gregory (Georgetown University, 2023)CDK4/6 inhibitors (CDKI) have improved disease control in hormone receptor-positive, HER2-negative metastatic breast cancer, but most patients still develop progressive disease. It is unclear to what extent host responses ...