Hypoxia Inducible Factor-1 in Cancer Immune Suppression

Hypoxia is a frequent feature of tumor microenvironment and contributes significantly to tumorigenesis and cancer progression. Furthermore, it is increasingly recognized that the transcription factor called hypoxia inducible factor (HIF)-1 also promotes cancer immunosuppression. HIF-1 is activated during hypoxia by stabilization of the subunit HIF- 1alpha. Alternatively, growth factor stimulation or proinflammatory cytokines can activate HIF-1 also under normoxic conditions. Hypoxia directly converts certain immune effector cells into suppressor cells. Monocytes are recruited into tumors, differentiate into macrophages and accumulate in hypoxic areas where they acquire immunosuppressive characteristics. As a consequence of HIF-1 activation, the production of tolerogenic factors derived from cancer cells as well as from immune suppressor cells is increased. Several of the most important immunosuppressive molecules are under the transcriptional control of HIF-1, including vascular endothelial growth factor, heme oxygenase-1, inducible nitric oxide synthase and cyclooxygenase-2. HIF-1 interacts with several other transcription factors which are crucial for immunosuppression such as Stat3 that is over-activated in many tumor cells and in immune suppressor cells. Some factors which are expressed as a consequence of hypoxia through HIF-1 contribute to HIF-1 stabilization and activation. Hypoxia and HIF-1 facilitate the initiation of the intra- tumoral immunosuppressive state and contribute to its stabilization in regulatory networks.