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Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer

Nano Research 2023年第4期16卷 5300-5310页

作者： Yang Liu William N.Crowe Lulu Wang W.Jeffrey Petty Amyn A.Habib Dawen Zhao Department of Biomedical Engineering Wake Forest University School of MedicineWinston-SalemNC 27157USA Department of Medicine Section on Hematology and OncologyWake Forest University School of MedicineWinston-SalemNC 27157USA Department of Neurology University of Texas Southwestern Medical Center and VA North Texas Medical CenterDallasTX 75390USA Department of Cancer Biology Wake Forest University School of MedicineWinston-SalemNC 27157USA

Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains *** emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer ***,only a fraction of lung cancer patients benefit from *** clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 *** report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer ***,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 ***,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing ***,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic *** conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.

关键词： locally advanced non-small cell lung cancer(LANSCLC) nanoparticle immunotherapeutic aerosol inhalation stimulator of interferon genes programmed death 1/programmed death-ligand 1(PD-1/PD-L1)blockade

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Fangchinoline induces antiviral response by suppressing STING degradation

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Journal of Pharmaceutical Analysis 2024年第6期14卷 902-913页

作者： Jinyong Wang Fang Xie Xin Jia Xuejiao Wang Lingdong Kong Yiying Li b Xue Liang Meiqi Zhang Yuting He Wandi Feng Tong Luo Yao Wang Anlong Xu School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing100029China School of Life Science Beijing University of Chinese MedicineBeijing100029China Beijing Key Laboratory of Drug Target Identification and New Drug Screening Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China

The stimulator of interferon genes(STING),an integral adaptor protein in the DNA-sensing pathway,plays a pivotal role in the innate immune response against ***,it presents a valuable therapeutic target for infectious diseases and *** observed that fangchinoline(Fan),a bis-benzylisoquinoline alkaloid(BBA),effectively impedes the replication of vesicular stomatitis virus(VSV),encephalomyocarditis virus(EMCV),influenza A virus(H1N1),and herpes simplex virus-1(HSV-1)in *** treatment significantly reduced the viral load,attenuated tissue inflammation,and improved survival in a viral sepsis mouse ***,Fan activates the antiviral response in a STING-dependent manner,leading to increased expression of interferon(IFN)and interferon-stimulated genes(ISGs)for potent antiviral effects in vivo and in ***,Fan interacts with STING,preventing its degradation and thereby extending the activation of IFN-based antiviral ***,our findings highlight the potential of Fan,which elicits antiviral immunity by suppressing STING degradation,as a promising candidate for antiviral therapy.

关键词： Fangchinoline Virus Type I interferons stimulator of interferon genes Protein degradation

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STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function

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Cellular & Molecular Immunology 2021年第3期18卷 632-643页

作者： Hee-Jin ChoiTaylor Ticer Yongxia Wu Chih-Hang Anthony Tang Corey Mealer David Bastian M.Hanief Sofi Linlu Tian Steven Schutt Hee-Jin Choi Taylor Ticer Mengmeng Zhang Xiaohui Sui Lei Huang Andrew L.Mellor Chih-Chi Andrew Hu Xue-Zhong Yu Microbiology&Immunology Medical University of South CarolinaCharlestonSCUSA Immunology Microenvironment&Metastasis ProgramThe Wistar InstitutePhiladelphiaPAUSA Translational and Clinical Research Institute Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK Department of Medicine Medical University of South CarolinaCharlestonSCUSA Hollings Cancer Center Medical University of South CarolinaCharlestonSCUSA

stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and ***,STING can also suppress tumor immunity and *** signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD ***,how STING regulates host hematopoietic APCs after allo-HCT remains *** utilized murine models of allo-HCT to assess the role of STING in hematopoietic ***-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched *** bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the ***,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell ***,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic ***,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in ***-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated *** pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD *** conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.

关键词： stimulator of interferon genes antigen-presenting cells allogeneic hematopoietic cell transplantation graft-versushost diseases hematopoietic stem-cell transplantation T cells

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Advances in the prerequisite and consequence of STING downstream signalosomes

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Medical Review 2024年第5期4卷 435-451页

作者： Xinliang Lu Xiaobing Li Lili Li Chuanhui Han Sirui Li Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital Zhejiang University School of MedicineHangzhouChina InvivoGen Ltd. Hong Kong Science and Technology ParksHong KongChina Center for Systems Medicine Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Suzhou Institute of Systems Medicine SuzhouJiangsuChina Peking University International Cancer Institute Peking University Cancer Hospital and InstituteHealth Science CenterPeking UniversityBeijing100084China Lineberger Comprehensive Cancer Center University of North Carolina at Chapel HillChapel HillNC 27599USA

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining *** from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed *** binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isﬁnely restricted by multiple degradation *** post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING *** experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell *** signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in *** advances have established the vital role of STING in immune surveil-lance as well as tumorigenic *** review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.

关键词： stimulator of interferon genes signalosomes cellular heterogeneity cancer therapeutics

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Cyclic Dinucleotides with Mixed Inosine That Activate hSTING Pathway

Cyclic Dinucleotides with Mixed Inosine That Activate hSTING...

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第十一届全国化学生物学学术会议

作者： Zhenghua Wang Chuanlin Wang Cancan Zhao Luyuan Li Zhen Xi Sate Key Laboratory of Elemento-Organic Chemistry and College of Chemistry Nankai University State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy Nankai University

Cyclic dinucleotides（CDNs） play key roles as second messengers and signaling molecules in bacteria and metazoans. In mammalian cells, CDNs could activate stimulator of interferon genes（STING） and induce type I interferon responses and other pro-inflammation cytokines, therefor possess great potentials to be of immunotherapeutic value for cancers and infectious diseases. Herein, we reported all the possibility of CDNs with inosine and four natural bases G, A, U, C combinations and 2’-5’ and 3’-5’ phosphodiester linkages combinations（Figure 1）. Following, the associated activity between the inosine mixed CDNs and the wild type hSTING or its SNPs（HAQ, R232 H, AQ, and R293 Q） inducing the production of interferon-β were measured with dual-luciferase reporter assay. It is hoped that this study will contribute to a deeper understanding of CDNs-based hSTING agonist in immunotherapy.

关键词： Cyclic dinucleotides(CDNs) Inosine stimulator of interferon genes interferon-β

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