Impairment of cytotoxic anti-tumor response by hypoxic stress (P2011)

Abstract

Abstract Hypoxia is a central hallmark of tumor microenvironment and a pivotal driving force of malignant progression. Although hypoxia has been reported to play a major role in the acquisition of tumor resistance to cell death, the molecular mechanisms that enable the survival of hypoxic cancer cells have not been fully elucidated. Recently, attention has focused on the mechanisms by which hypoxic tumour cells alter their transcriptional profiles allowing them to persist under conditions of hypoxic stress. Here we demonstrate that NANOG, a transcription factor associated with stem cell self renewal, is induced under hypoxic conditions at both transcriptional and translational levels and contributes to the decreased susceptibility of target cells to specific cytotoxic T lymphocyte (CTL)-mediated lysis. The precise mechanisms by which NANOG regulates tumor susceptibility to CTL-mediated lysis will be discussed. In addition since we have demonstrated that in vivo inhibition of hypoxia restores cytotoxic T lymphocyte activity and promotes in vivo tumor regression, we will also discuss the relationship between hypoxic stress and survival pathways associated with hypoxic stress in particular the emergence of cancer stem cells and autophagy induction.