STING ligand-1

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation

Background: Resistance to an immune checkpoint inhibitor (ICI) is a major obstacle in cancer immunotherapy. The causes of ICI resistance include major histocompatibility complex (MHC)/histocompatibility locus antigen (HLA) class I loss, neoantigen loss, and incomplete antigen presentation. Elimination by natural killer (NK) cells would be expected to be an effective strategy for the treatment of these ICI-resistant tumors. We previously demonstrated that a lipid nanoparticle containing a stimulator of an interferon gene (STING) agonist (STING-LNP) efficiently induced antitumor activity via the activation of NK cells. Thus, we evaluated the potential of reducing ICI resistance by STING-LNPs.
Methods: Lung metastasis of a B16-F10 mouse melanoma was used as an anti-programmed cell death 1 (anti-PD-1)-resistant mouse model. The mice were intravenously injected with the STING-LNP and the mechanism responsible for the improvement of anti-PD-1 resistance by the STING-LNPs was analyzed by RT-qPCR and flow cytometry. The dynamics of STING-LNP were also investigated.
Results: Although anti-PD-1 monotherapy failed to induce an antitumor effect, the combination of the STING-LNP and anti-PD-1 exerted a synergistic antitumor effect. Our results indicate that the STING-LNP treatment significantly increased the expression of CD3, CD4, NK1.1, PD-1 and interferon (IFN)-γ in lung metastases. This change appears to be initiated by the type I IFN produced by liver macrophages that contain the internalized STING-LNPs, leading to the systemic activation of NK cells that express PD-1. The activated NK cells appeared to produce IFN-γ, resulting in an increase in the expression of the PD ligand 1 (PD-L1) in cancer cells, thus leading to a synergistic antitumor effect when anti-PD-1 is administered.
Conclusions: We provide a demonstration to show that a STING-LNP treatment can overcome PD-1 resistance in a B16-F10 lung metastasis model. The mechanism responsible for this indicates that NK cells are activated by stimulating the STING pathway which, in turn, induced the expression of PD-L1 on cancer cells. Based on the findings reported herein, the STING-LNP represents a promising candidate for use in combination therapy with anti-PD-1-resistant tumors.

STING agonist enhances the efficacy of programmed death-ligand 1 monoclonal antibody in breast cancer immunotherapy by activating the interferon-β signalling pathway

This study aimed to explore the role of a stimulator of interferon (IFN) gene (STING) agonist in breast cancer (BCa) immunotherapy. Clinical samples were collected from 37 patients with BCa. A tumor-bearing mouse model was established by injecting 4T1 cells into the mammary fat pad of mice. STING agonist and atezolizumab were injected in the mice twice a week for 2 weeks. Peripheral blood, tumor mass, lung, liver, brain cortex and kidney samples of the tumor-bearing mice were collected. Anti-IFN alpha receptor subunit 1 (IFNAR1) was used to treat 4T1 cells. Tumor tissues of patients with BCa exhibited lower STING and high programmed cell death protein 1 and programmed death-ligand 1 protein expressions. The STING agonist inhibited 4T1 cell growth in mice (P < 0.001) and increased the IFN-β level and phosphorylation of STING, TBK1, IRF3 and STAT1 in tumor mass of tumor-bearing mice (P < 0.001). It synergized with atezolizumab to inhibit 4T1 cell growth in mice and increased tumor necrosis factor-α, IFN-β, interleukin-10 and IFN-γ levels in the peripheral blood and tumor mass (P < 0.01). It synergized with atezolizumab to increase CD8+ cytotoxic T cells and decrease FOXP3+ Treg cells in the tumor-bearing mouse model. The STING agonist was nontoxic to the lung, liver, brain cortex and kidney. Anti-IFNAR1 reversed the STING agonist promotion on TBK1, IRF3 and STAT1 phosphorylation in 4T1 cells (P < 0.01). STING agonists enhance the efficacy of atezolizumab in BCa immunotherapy by activating the IFN-β signaling pathway.

Small molecules targeting the innate immune cGAS?STING?TBK1 signaling pathway

Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors (ICIs) have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity. Particularly, the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S. Food and Drug Administration (FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies. However, the majority of cancers have low clinical response rates to these ICIs due to poor tumor immunogenicity. Indeed, the cyclic guanosine monophosphate-adenosine monophosphate synthase?stimulator of interferon genes?TANK-binding kinase 1 (cGAS?STING?TBK1) axis is now appreciated as the major signaling pathway in innate immune response across different species. Aberrant signaling of this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection and cancers. In this perspective, we provide an updated review on the latest progress on the development of small molecule modulators targeting the cGAS?STING?TBK1 signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy. Meanwhile, highlights on the clinical candidates, limitations and challenges, as well as future directions in this field are also discussed. Further, small molecule inhibitors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.

Emerging views of mitophagy in immunity and autoimmune diseases

Mitophagy is a vital form of autophagy for selective removal of dysfunctional or redundant mitochondria. Accumulating evidence implicates elimination of dysfunctional mitochondria as a powerful means employed by autophagy to keep the immune system in check. The process of mitophagy may restrict inflammatory cytokine secretion and directly regulate mitochondrial antigen presentation and immune cell homeostasis. In this review, we describe distinctive pathways of mammalian mitophagy and highlight recent advances relevant to its function in immunity. In addition, we further discuss the direct and indirect evidence linking mitophagy to inflammation and autoimmunity underlying the pathogenesis of autoimmune diseases including inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC).Abbreviations: AICD: activation induced cell death; AIM2: absent in melanoma 2; ALPL/HOPS: alkaline phosphatase, biomineralization associated; AMA: anti-mitochondrial antibodies; AMFR: autocrine motility factor receptor; ATG: autophagy-related; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain containing; CASP1: caspase 1; CD: Crohn disease; CGAS: cyclic GMP-AMP synthase; CXCL1: C-X-C motif chemokine ligand 1; DEN: diethylnitrosamine; DLAT/PDC-E2: dihydrolipoamide S-acetyltransferase; DNM1L/Drp1: dynamin 1 like; ESCRT: endosomal sorting complexes required for transport; FKBP8: FKBP prolyl isomerase 8; FUNDC1: Fun14 domain containing 1; GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box 1; HPIV3: human parainfluenza virus type 3; IBD: inflammatory bowel diseases; IEC: intestinal epithelial cell; IFN: interferon; IL1B/IL-1β: interleukin 1 beta; iNK: invariant natural killer; IRGM: immunity related GTPase M; LIR: LC3-interacting region; LPS: lipopolysaccharide; LRRK2: leucine rich repeat kinase 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARCH5: membrane associated ring-CH-type finger 5; MAVS: mitochondrial antiviral signaling protein; MDV: mitochondria-derived vesicle; MFN1: mitofusin 1; MHC: major histocompatibility complex; MIF: macrophage migration inhibitory factor; mtAP: mitochondrial antigen presentation; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; mtROS: mitochondrial ROS; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; NFKB/NF-?B: nuclear factor kappa B subunit; NK: natural killer; NLR: NOD-like receptor; NLRC4: NLR family CARD domain containing 4; NLRP3: NLR family pyrin domain containing 3; OGDH: oxoglutarate dehydrogenase; OMM: outer mitochondrial membrane; OPTN: optineurin; ox: oxidized; PARK7: Parkinsonism associated deglycase; PBC: primary biliary cirrhosis; PEX13: peroxisomal biogenesis factor 13; PHB/PHB1: prohibitin; PHB2: prohibitin 2; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced kinase 1; PLEKHM1: pleckstrin homology and RUN domain containing M1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RAB: member RAS oncogene family; RHEB: Ras homolog: mTORC1 binding; RIPK2: receptor interacting serine/threonine kinase 2; RLR: DDX58/RIG-I like receptor; ROS: reactive oxygen species; SBD: small bile ducts; SLC2A1/GLUT1: solute carrier family 2 member 1; SLE: systemic lupus erythematosus; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TCR: T cell receptor; TFAM: transcription factor A: mitochondrial; Th17: T helper 17; TLR9: toll like receptor 9; TMEM173/STING: transmembrane protein 173; TNF/TNF-α: tumor necrosis factor; Ub: ubiquitin; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WIPI: WD repeat domain: phosphoinositide interacting; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.