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Investigating the Effect of AMPK Activation on T Cell-mediated Anti-tumour Immunity

Alison Wong

出版	McGill University Libraries, 2018
URL	http://books.google.com.hk/books?id=_j-XwgEACAAJ&hl=&source=gbs_api

註釋

"T cells are important orchestrators of host defense against pathogen infections as well as damaged tissue. T cells play an especially important role in cancer immunosurveillance, although tumour cells are frequently able to evade immune destruction through immunosuppressive mechanisms. In order to enhance T cell anti-tumour responses, some of the most successful immunotherapy techniques involve enhancing T cell metabolism. AMPK is an energy sensor that is required for regulating T cell metabolic plasticity, and emerging evidence has shown that activating AMPK may enhance T cell-mediated anti-tumour immunity. However, many of the current methods used to activate AMPK are indirect, and therefore there is no direct evidence showing the effect of activating AMPK on T cell function and anti-tumour immunity. Therefore, we hypothesized that AMPK activity is required for T cell-mediated anti-tumour immunity. We have found that activating AMPK in T cells can modulate T cell effector function in vitro, and anti-tumour immunity in vivo. Using a pharmacological method of activating AMPK, we found that T cell effector function was unchanged in vitro and in vivo, but T cells did have a growth advantage in nutrient-limiting conditions. Using the FLCN KO model of activating AMPK, we found that both AMPK and mTORC1 signalling were increased in T cells, as well as cytokine production and proliferation. In vivo, we observed a weaker FLCN KO T cell primary immune response towards L. monocytogenes. In the tumour model context, tumour growth was decreased in FT mice, although tumour growth was greater in mice receiving an adoptive transfer of FLCN KO T cells. Altogether, this research shows that important T cell functions can be enhanced by AMPK activation, and demonstrates the context-dependent role of AMPK in T cell function and in anti-tumour immunity"--