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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 poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant 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 blockade.We 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 immunity.Intriguingly,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 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In 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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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 autoimmunity.However,STING can also suppress tumor immunity and autoimmunity.STING 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 initiation.However,how STING regulates host hematopoietic APCs after allo-HCT remains unknown.We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs.STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT.Using bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease.Furthermore,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses.Mechanistically,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic cells.Consistently,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in mice.STING-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated GVHD.Using 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 mortality.In 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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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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