Self-assembled cGAMP-STINGΔTM signaling complex as a bioinspired platform for cGAMP delivery

A bioinspired approach was developed for STING agonist delivery with STINGΔTM as a functional carrier. The stimulator of interferon (IFN) genes (STING) pathway constitutes a highly important part of immune responses against various cancers and infections. Consequently, administration of STING agonists such as cyclic GMP-AMP (cGAMP) has been identified as a promising approach to target these diseases. In cancer cells, STING signaling is frequently impaired by epigenetic silencing of STING; hence, conventional delivery of only its agonist cGAMP may be insufficient to trigger STING signaling. In this work, while expression of STING lacking the transmembrane (TM) domain is known to be unresponsive to STING agonists and is dominant negative when coexpressed with the full-length STING inside cells, we observed that the recombinant TM-deficient STING protein complexed with cGAMP could effectively trigger STING signaling when delivered in vitro and in vivo, including in STING-deficient cell lines. Thus, this bioinspired method using TM-deficient STING may present a universally applicable platform for cGAMP delivery.

[1]  B. Sankaran,et al.  A Conserved PLPLRT/SD Motif of STING Mediates the Recruitment and Activation of TBK1 , 2019, Nature.

[2]  Zhijian J. Chen,et al.  Structural basis of STING binding with and phosphorylation by TBK1 , 2019, Nature.

[3]  Mark Kelley,et al.  Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy , 2018, Nature Nanotechnology.

[4]  Zhijian J. Chen,et al.  Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP , 2019, Nature.

[5]  Zhengfan Jiang,et al.  STING directly activates autophagy to tune the innate immune response , 2018, Cell Death & Differentiation.

[6]  Seema Patel,et al.  TMEM173 variants and potential importance to human biology and disease , 2018, Genes & Immunity.

[7]  Kit-San Yuen,et al.  A novel transcript isoform of STING that sequesters cGAMP and dominantly inhibits innate nucleic acid sensing , 2018, Nucleic acids research.

[8]  Lei Jin,et al.  The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans , 2018, PLoS pathogens.

[9]  George E. Katibah,et al.  Comment on “The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele” , 2017, The Journal of Immunology.

[10]  Lei Jin,et al.  Response to Comment on “The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele” , 2017, The Journal of Immunology.

[11]  K. Ishibashi,et al.  Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site , 2017, Cancer Immunology, Immunotherapy.

[12]  David J Mooney,et al.  Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy , 2017, Advanced biosystems.

[13]  Lei Jin,et al.  The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele , 2017, The Journal of Immunology.

[14]  G. Barber,et al.  Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis. , 2016, Cancer research.

[15]  T. Gajewski,et al.  The host STING pathway at the interface of cancer and immunity. , 2016, The Journal of clinical investigation.

[16]  A. Poltorak,et al.  Cutting Edge: Novel Tmem173 Allele Reveals Importance of STING N Terminus in Trafficking and Type I IFN Production , 2016, The Journal of Immunology.

[17]  V. Hornung,et al.  STING Signaling the enERGIC Way. , 2015, Cell host & microbe.

[18]  Nan Yan,et al.  STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease. , 2015, Cell host & microbe.

[19]  Jianzhu Chen,et al.  Persistent Antigen and Prolonged AKT–mTORC1 Activation Underlie Memory CD8 T Cell Impairment in the Absence of CD4 T Cells , 2015, The Journal of Immunology.

[20]  Gregory L. Szeto,et al.  Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants. , 2015, The Journal of clinical investigation.

[21]  D. Pardoll,et al.  STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade , 2015, Science Translational Medicine.

[22]  G. Barber,et al.  Diverse roles of STING-dependent signaling on the development of cancer , 2015, Oncogene.

[23]  Ying Wang,et al.  STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. , 2014, Immunity.

[24]  D. Kanne,et al.  Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants , 2013, Therapeutic advances in vaccines.

[25]  Zhijian J. Chen,et al.  Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. , 2013, Molecules and Cells.

[26]  G. Cheng,et al.  Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. , 2012, Immunity.

[27]  Zhijian J. Chen,et al.  STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway , 2012, Science Signaling.

[28]  Yoshihiro Hayakawa,et al.  STING is a direct innate immune sensor of cyclic-di-GMP , 2011, Nature.

[29]  Ivana V. Yang,et al.  Identification and Characterization of a Loss-of-Function Human MPYS Variant , 2010, Genes and Immunity.

[30]  G. Barber,et al.  STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity , 2009, Nature.

[31]  A. Facciabene,et al.  Individual mouse analysis of the cellular immune response to tumor antigens in peripheral blood by intracellular staining for cytokines. , 2006, Journal of immunological methods.