Emerging role of RNA sensors in tumor microenvironment and immunotherapy

Yang, Rui; Yu, Sihui; Xu, Tianhan; Zhang, Jiawen; Wu, Sufang

doi:10.1186/s13045-022-01261-z

Cited by 14 publications

(17 citation statements)

References 178 publications

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“…RIG-I is well established to be one of the critical intracellular sensors for host recognition of RNA virus infection and subsequent induction of type I interferon (IFN) production in innate immune cells. It contains a C-terminal helicase domain to recognize cytoplasmic viral RNA and two N-terminal tandem caspase-recruiting domains (CARDs) to activate downstream type I IFN production [ 11 , 12 ]. Other than RIG-I expression in immune cells, we previously found that RIG-I expression was mainly located in parenchymal hepatocytes in the liver, but not in mesenchymal cells [ 13 ], suggesting the potential roles of RIG-I in liver functions and diseases.…”

Section: Introductionmentioning

confidence: 99%

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

Zhou

Jia

et al. 2022

J Hematol Oncol

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Background Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study. Methods DEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation. Results We interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models. Conclusions Decreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.

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Section: Introductionmentioning

confidence: 99%

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

Zhou

Jia

et al. 2022

J Hematol Oncol

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“…However, the role of MDA5-MAVS pathway in tumor immunity is still very complex, and many questions remain unanswered. Recently, increasing evidences have illustrated how the innate immune pathway in the tumor microenvironment changes tumorigenesis in different tumors, thus affecting the subsequent design of effective immunotherapy trials ( 83 , 84 ).…”

Section: Discussionmentioning

confidence: 99%

The intersection molecule MDA5 in Cancer and COVID-19

Jin

Cao

et al. 2022

Front. Immunol.

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The connections between pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) constitutes the crucial signaling pathways in the innate immune system. Cytoplasmic nucleic acid sensor melanoma differentiation-associated gene 5 (MDA5) serves as an important pattern recognition receptor in the innate immune system by recognizing viral RNA. MDA5 also plays a role in identifying the cytoplasmic RNA from damaged, dead cancer cells or autoimmune diseases. MDA5’s recognition of RNA triggers innate immune responses, induces interferon (IFN) response and a series of subsequent signaling pathways to produce immunomodulatory factors and inflammatory cytokines. Here we review the latest progress of MDA5 functions in triggering anti-tumor immunity by sensing cytoplasmic dsRNA, and recognizing SARS-CoV-2 virus infection for antiviral response, in which the virus utilizes multiple ways to evade the host defense mechanism.

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“…LGP2 may repress RIG-I signaling through multiple mechanisms, such as interruption of the interaction between RIG-I and MAVS [45,46], inhibition of Dicer processing of long dsRNA [47], prevention of viral dsRNA binding to RIG-I [48], and suppression of TRIM25-mediated RIG-I ubiquitination [49]. On the other hand, accumulating evidence indicates that LGP2 cooperates with MDA5 to augment IFN response [50][51][52]. LGP2 promotes MDA5 nucleation and the conversion of MDA5 to an active conformation [50].…”

Section: An Overview Of Rlrs Signalingmentioning

confidence: 99%

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

et al. 2023

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RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.

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Emerging role of RNA sensors in tumor microenvironment and immunotherapy

Cited by 14 publications

References 178 publications

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

The intersection molecule MDA5 in Cancer and COVID-19

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

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