RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation

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 HIF1α. 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 IFNα, 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 , boosted anti-melanoma NK- and CD8 T-cell attack, and augmented 3pRNA antitumor efficacy 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 IFNα receptor. RIG-I function could be fortified under hypoxia by the combined use of 3pRNA with antioxidants..

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

“…One explanation could be that RIG-I becomes activated through endogenous transposable elements originally stemming from viral species, such as retrotransposons. 17,55 In addition, RIG-I-expressing (ISG signature-positive) tumors may be susceptible to the loss of ADAR1, 31 which may offer new therapeutic prospects in a subset of patients. 51 Moreover, epigenetic cancer treatment with DNA-demethylating agents triggers cytoplasmic RNA sensing and viral mimicry that involves endogenous retroviral elements.…”

“…This concept bases on the notion that the provision of high-dose ligands from an outside source may activate RIG-I signaling to a greater extent than endogenous ligands in the tumor microenvironment, thus generating high-level immunity and overcoming immunosuppression and exhaustion. 17,55 In addition, RIG-I-expressing (ISG signature-positive) tumors may be susceptible to the loss of ADAR1, 31 which may offer new therapeutic prospects in a subset of patients.…”

Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy

“…5C). Since RLH signaling induces expression of T cell-recruiting chemokines (37,38), we asked to which extent chemokine release was retained in IFN-resistant Ma-Mel-61g cells. Besides enhanced HLA-I APM expression ( Figure 6A, Supplemental Figure 4A), 3pRNA-transfected Ma-Mel-61g cells induced de novo transcription of IFNβ (Supplemental Figure 4B) and specific chemokine genes (CCL2, CCL4, CCL5, CXCL10) ( Figure 6B).…”

Natural killer cells in cancer biology and therapy

“…Previous findings indicated that besides promoting tumorigenesis and cancer progression, hypoxia also stimulates NK cell formation via HIF-1α, initiating a conflict between suppressing and activating this signal [ 182 ]. Studies have also shown that low O 2 in TME harms the function of NK cells by downregulating activating signals such as NKG2D, NKp30 and CD16, thereby limiting cytokine production and cytotoxicity and resulting in metastasis [ 183 , 184 ]. In addition to regulating intracellular signals directly, the hypoxic microenvironment could degrade NK cell-secreted functional molecules such as granzyme B [ 185 ], together with CTL-based immunity, which is partly rescued by IL-2 [ 186 , 187 ].…”