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Engel, Christina; Brügmann, Grethe; Lambing, Silke; Mühlenbeck, Larissa H.; Marx, Samira; Hagen, Christian; Horvath, Dorottya; Goldeck, Marion; Ludwig, Janos; Herzner, Anna-Maria; Drijfhout, Jan W.; Wenzel, Daniela; Coch, Christoph; Tüting, Thomas; Schlee, Martin; Hornung, Veit; Hartmann, Gunther; Boorn, Jasper G. van den (2017): RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation. In: Cancer Immunology Research, Vol. 5, No. 6: pp. 455-467
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Abstract

A hypoxic tumor microenvironment is linked to poor prognosis. It promotes tumor cell dedifferentiation and metastasis and desensitizes tumor cells to type-I IFN, chemotherapy, and irradiation. The cytoplasmic immunoreceptor retinoic acid-inducible gene-I (RIG-I) is ubiquitously expressed in tumor cells and upon activation by 5'-triphosphate RNA (3pRNA) drives the induction of type I IFN and immunogenic cell death. Here, we analyzed the impact of hypoxia on the expression of RIG-I in various human and murine tumor and nonmalignant cell types and further investigated its function in hypoxic murine melanoma. 3pRNA-inducible RIG-I-expression was reduced in hypoxic melanoma cells compared with normoxic controls, a phenomenon that depended on the hypoxia-associated transcription factor HIF1 alpha. Still, RIG-I functionality was conserved in hypoxic melanoma cells, whereas responsiveness to recombinant type-I IFN was abolished, due to hypoxia-induced loss of type I IFN receptor expression. Likewise, RIG-I activation in hypoxic melanoma cells, but not exposure to recombinant IFN alpha, provoked melanocyte antigen-specific CD8(+) T-cell and NK-cell attack. Scavenging of hypoxia-induced reactive oxygen species by vitamin C restored the inducible expression of RIG-I under hypoxia in vitro, boosted in vitro anti-melanoma NK- and CD8(+) T-cell attack, and augmented 3pRNA antitumor efficacy in vivo. These results demonstrate that RIG-I remains operational under hypoxia and that RIG-I function is largely insensitive to lower cell surface expression of the IFN alpha receptor. RIG-I function could be fortified under hypoxia by the combined use of 3pRNA with antioxidants. (C)2017 AACR.