Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs

Abstract

Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in�vitro

“…Recently, Ranoa et al showed that depletion of RIG-I protected mice from death following to total body irradiation (21). They also showed that ionizing radiation increased the RIG-I expression, not MDA5 expression, and that RIG-I recognize small endogenous noncoding RNA induced by ionizing radiation, which resulted in the activation of IFN signaling through MAVS.…”

Stimulating Innate Immunity to Enhance Radiation Therapy–Induced Tumor Control

“…A type I IFN gene signature is induced by chemotherapy and radiation therapy in some patients. This type I IFN gene signature is associated with improved outcome following neoadjuvant chemotherapy in breast cancer patients 111 . However, this interferon signature is expressed in a broad array of cancer cell lines, and predicts a poor response to chemotherapy and radiation therapy in patients with breast cancer 143 and glioblastoma 144 .…”

“…During infection, the entry of unmodified RNA into the cytoplasm, triggers these sensors and activates the production of type I IFN 110 . RIG-I 111 and LGP2 112 , but not MDA5, 113 also can detect endogenous nuclear material that has translocated to the cytoplasm following radiation therapy. Irradiated cells activate type I IFN production in a RIG-I dependent manner and mice lacking RIG-I were protected against gastrointestinal epithelial cell death following total body radiation 111 .…”

“…RIG-I 111 and LGP2 112 , but not MDA5, 113 also can detect endogenous nuclear material that has translocated to the cytoplasm following radiation therapy. Irradiated cells activate type I IFN production in a RIG-I dependent manner and mice lacking RIG-I were protected against gastrointestinal epithelial cell death following total body radiation 111 . By contrast, LGP2 has an opposite effect and suppresses type I IFN induced by radiation therapy 112 .…”

The intersection of radiotherapy and immunotherapy: Mechanisms and clinical implications

“…In addition, RIG-1, MDA5 and LGP2 are RNA sensors that act through IRF3 and NF-κB to induce pro-inflammatory cytokines. Radiation also activates these RNA sensors, which have been shown to be necessary for the induction of Type I IFN after DNA damage (13). In addition to being directly produced by irradiated cells, it is likely secondary messengers such as cGAMP are transferred via gap junctions to stimulate the STING pathway in non-irradiated cells (14).…”