Role of LIGHT in the immunological control of cancer
This project is to examine the therapeutic potential of LIGHT (TNFSF14) in the control of cancer in experimental models in mice to determine if regulating this cytokine can be used to treat human cancer.
Innate and adaptive immune systems play a critical role for the elimination of spontaneously arising tumours, as well as infected cells. Malignant cells are often able to escape from immune surveillance as these cells are not recognized as foreign by the body’s own immune system. For this reason, it is critical to develop effective ways to activate the immune system to recognize the affected cells. A group of specialized proteins known as co-stimulatory molecules can be activated to facilitate cancer cell recognition by the immune system. Recent studies have shown that LIGHT, which has both pro-inflammatory and co-stimulatory functions, is highly effective at inducing anti-tumour cell responses against epithelial tumours. LIGHT can perform two distinctive functions essential for tumour rejection: (i) to organize a special microenvironment to attract immune cells into tumour tissue, and (ii) to activate these infiltrating cells to differentiate into effector cells, which can destroy the cancer cells. The focus of this project is two folds. First, it will study the effects of different forms of LIGHT, cytoplasmic, membrane and soluble, on the survival of EL4 tumour cells using our established in vivo tumour rejection mouse model. EL4 tumour cells that have been engineered to express different forms of LIGHT will be tested in the tumour rejection model. The results obtained from these experiments will give us insight into the contributions of the different forms of LIGHT in inducing tumour rejection.
Second, this project will focus on the molecular mechanism of LIGHT-mediated anti-tumour activities. The functional requirement for LIGHT in mediating tumour rejection will be examined using recombinant soluble receptors, which block binding of LIGHT to its cellular receptors, viz. LTR-Fc, HVEM-Fc, or DcR3-Fc, to the epithelial tumours. This project will provide important mechanistic insight into the role LIGHT in control of cancer, and how the TNF superfamily cosignalling networks can be manipulated to enhance immunity to tumours.
Cellular immunology, molecular engineering of cytokine expression in tumour cells, production of soluble inhibitors of cytokines, protein engineering and expression using recombinant baculovirus and retrovirus.Additional supervisor for this project is Dr Timothy Cheung
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The opportunity ID for this research opportunity is: 752
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