miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS

Abstract

The mechanisms by which hypoxic tumors evade immunological pressure and anti-tumor immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR25 and miR93, are important for establishing an immunosuppressive tumor microenvironment by down-regulating expression of the DNA-sensor cGAS. Mechanistically, miR25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS upon hypoxia. This allows hypoxic tumor cells to escape immunological responses induced by damage-associated molecular pattern molecules (DAMPs), specifically the release of mtDNA. Moreover, restoring cGAS expression results in an anti-tumor immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harboring high levels of miR25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumor progression, and reveals a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumor microenvironment, thus unveiling potential new therapeutic strategies.

miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway

“…Recently, cGAS and STING were identified as intracellular sensors that activate the interferon pathway and mediate host defense; this role might be influenced by miRNAs [12,32,49]. Wu showed that miR25/93 mediates hypoxia-induced immunosuppression by repressing cGAS [51], and Huang revealed that miR-24 regulates STING in rats [15]. Similarly, our results showed that miR-378b could bind TBKBP1 and increase the expression of TBK1 to activate the cGAS/STING pathway.…”

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

“…We further verified that ZNF205‐AS1 increased EGR4 mRNA stability, and therefore up‐regulated EGR4 expression. microRNAs (miRNAs) are well‐known to bind the 3’UTR of target mRNAs and induce the degradation and/or translation inhibition of target mRNAs . The interaction between ZNF205‐AS1 transcript and EGR4 mRNA 3’UTR may protect EGR4 mRNA from miRNAs‐induced degradation, which need further investigation.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[105][106][107][108][109][110] Accordingly, RCD can no longer be perceived as immunogenic when: (1) the intracellular stress responses regulating the emission of ICD-associated DAMPs are pharmacologically or genetically ablated in cancer cells; or (2) when the molecular machinery dedicated to DAMP detection is inhibited or ablated. 13,44,84,91,93,97 Moreover, ICD-driven immunity can no longer operate in the presence of general immunological defects, 111 such as (1) an intrinsically low antigenicity of cancer cells, owing to low levels of TAAs or downregulation of MHC Class I molecules [112][113][114][115][116][117][118][119] ; (2) an increased immunological tolerance of the host, secondary to increased amounts of immunosuppressive cytokines, [120][121][122][123][124][125][126][127][128] or inhibitors of chemotaxis, [129][130][131][132][133][134] increased tumor infiltration by immunosuppressive cell populations, [135][136][137][138][139][140]…”