Hypoxia Induces Escape from Innate Immunity in Cancer Cells via Increased Expression of ADAM10: Role of Nitric Oxide

Abstract

One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Here, we show that hypoxia induces tumor cell resistance to lysis mediated by immune effectors and that this resistance to lysis occurs via a hypoxiainducible factor-1 (HIF-1)-dependent pathway linked to increased expression of the metalloproteinase ADAM10. This enzyme is required for the hypoxia-induced shedding of MHC class I chain-related molecule A (MICA), a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells. Indeed, our findings show a mechanistic link between hypoxia-induced accumulation of the a-subunit of HIF-1 (HIF-1a), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors. Nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF1a and with the hypoxia-induced upregulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. Furthermore, treatment of tumor-bearing mice with nitroglycerin, a nitric oxide mimetic, attenuated tumor growth by a mechanism that relied upon innate immune effector cells. Together, these findings reveal a novel mechanism by which the hypoxic tumor microenvironment contributes to immune escape in cancer, lending support to potential immunotherapeutic strategies involving the use of nitric oxide mimetics. Cancer Res; 71(24); 7433-41. Ó2011 AACR.

Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1α-dependent manner

“…The present and previous studies (18,19) show that hypoxia decreases the susceptibility of tumor cells by reducing the expression of cell surface MICA, although the mechanisms of the reduction in the expression of cell surface MICA differ. Hypoxia has been reported to attenuate the antitumor activity of cytotoxic immune cells (17).…”

“…Several studies have shown that hypoxia-induced inhibition of NO production is linked to hypoxia-induced tumor invasion, metastasis, resistance to chemotherapy and shedding of cell surface MICA (18)(19)(20)(21)(22). In this study, hypoxia also induced the inhibition of NO production in osteosarcoma cells.…”

“…In this study, we examined the effects of hypoxia on the expression of the cell surface NKG2D ligands of osteosarcoma cells, the secretion of soluble NKG2D ligands and the role of HIF-1α in the hypoxia-induced effects. Several studies have previously shown such hypoxia-induced effects to be produced by the hypoxia-induced inhibition of the nitric oxide (NO) signaling pathway (18)(19)(20)(21)(22) and that NO modulates hypoxia-induced cellular events (23,24). Therefore, we also examined the role of NO in hypoxia-induced effects.…”

“…On the other hand, tumor cells produce soluble forms of NKG2D ligands by proteolytic cleavage of their extracellular domains (8,(10)(11)(12)(13). Soluble forms of NKG2D ligands interfere with the binding of NKG2D ligands on the surface of tumor cells to NKG2D receptors on the surface of cytotoxic immune cells, and the binding of soluble NKG2D ligands to NKG2D receptors downregulates the NKG2D receptors on the surface of cytotoxic immune cells (8,(13)(14)(15)(16) Regarding the effects of hypoxia on immune surveillance, there are many studies on the hypoxia-induced inhibition of cytotoxic activity of immune cells (17); however, only a few studies have addressed the effects of hypoxia on immune escape by tumor cells (18,19). In this study, we examined the effects of hypoxia on the expression of the cell surface NKG2D ligands of osteosarcoma cells, the secretion of soluble NKG2D ligands and the role of HIF-1α in the hypoxia-induced effects.…”

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

“…NO suppresses MMP-9 expression by destabilizing its mRNA in rat mesangial cells (35), whereas inhibition of NOS has been found to promote cytokine-induced MMP-9 expression in aortic smooth muscle cells (36) and exotoxin-mediated MMP expression in iNOS -/-mice (37). Furthermore, NO may inhibit hypoxia-induced expression of ADAM10 (38). Therefore, it is hypothesized that NO may affect the expression of other ADAMs, including ADAM12.…”