Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Dr. Gunaratnam

Abstract

The phagocytic clearance of apoptotic cells –efferocytosis- is essential for maintaining immune tissue homeostasis. Uncleared apoptotic cells can undergo secondary necrosis releasing endogenous danger signals such as high mobility group box protein 1 (HMGB1) into the extracellular milieu, triggering the innate immune system. Kidney Injury Molecule -1 (KIM-1) is a phosphatidylserine (PS) receptor that has been shown to confer on proximal tubular epithelial cells (PTECs) the ability to clear apoptotic cells during acute kidney injury. KIM-1 is overexpressed by various human tumours including renal clear cell carcinoma (RCC), though the impact of this on tumour progression is not known. Importantly, RCC tumours are highly resistant to chemotherapies and radiotherapies that are known to concurrently induce tumour cell apoptosis and trigger an immune response to the dying cancer cells. In this thesis I show, for the first time, that endogenous KIM-1 expressed by human RCC cell lines enables them to become semi-professional phagocytes and efficiently engulf apoptotic and necrotic cells. Using siRNA-mediated knockdown of KIM-1 expression in RCC cells, we show that KIM-1-dependent phagocytosis by RCC cells significantly reduced the leakage of HMGB1 from apoptotic cells undergoing secondary necrosis or necrotic cells. In addition, we demonstrate that the failure to clear dying cells by RCC cells was associated with enhanced activation of primary dendritic cells when they were exposed to the conditioned medium from RCC cells fed apoptotic or necrotic cells. Therefore, we propose that the upregulation of KIM-1 expression by cancers may allow them to evade the immune system and immunogenic cell death by chemotherapy and thereby makes KIM-1 a potential therapeutic target.

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