Mechanisms of hypoxia‐induced immune escape in cancer and their regulation by nitric oxide (85.1)

Abstract

The acquired ability of tumour cells to avoid destruction by immune effector mechanisms (immune escape) is important to malignant progression. Also associated with malignant progression is tumour hypoxia, which induces aggressive phenotypes such as invasion, metastasis and drug resistance in cancer cells. Our studies revealed that hypoxia contributes to escape from innate immunity by increasing tumour cell expression of the metalloproteinase ADAM10 in a manner dependent on accumulation of the alpha subunit of the transcription factor hypoxia‐inducible factor‐1 (HIF‐1α). Increased ADAM10 expression leads to shedding of the NK cell‐activating ligand, MICA, from the surface of tumour cells, thereby resulting in resistance to NK cell‐mediated lysis. Our more recent studies demonstrated that hypoxia, also via HIF‐1α accumulation, increases the expression of the inhibitory co‐stimulatory ligand PD‐L1 on tumour cells. Elevated PD‐L1 expression leads to escape from adaptive immunity via increased apoptosis of CD8+ cytotoxic T lymphocytes. We have also shown that activation of nitric oxide signalling inhibits hypoxia‐induced escape from innate and adaptive immunity at least partly by interfering with HIF‐1α accumulation. These findings indicate that approaches designed to interfere with tumour cell adaptations to hypoxia may have useful applications as adjuvants to immunotherapy.