The Age of Cyclic Dinucleotide Vaccine Adjuvants

Himanshu Gogoi, Samira Mansouri, Lei Jin, Himanshu Gogoi, Samira Mansouri, Lei Jin

Abstract

As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck's CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro's CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

Keywords: anti-tumor immunity; cyclic dinucleotides; vaccine adjuvants.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The mode of action of cyclic dinucleotides (CDNs) in dendritic cells (DCs). Immunized CDNs are taken up by pinocytosis or phagocytosis by dendritic cells in vivo. In the cytoplasm, CDNs bind to STING dimers located on the endoplasmic reticulum (ER) membrane, which undergoes conformational changes and activation. The STING (Stimulator of interferon genes) activation recruits kinases TANK binding kinase 1 (TBK 1) or IκB kinase (Iκκε). TBK 1 phosphorylates interferon regulatory factor 3 (IRF3), which dimerizes and translocates to the nucleus to activate type I IFNs. Iκκε phosphorylates nuclear factor-κB (NF-κB) inhibitor IκBα leading to dissociation of IκBα from NF-κB and translocation of the later to the nucleus to activate pro-inflammatory cytokines such as TNF-α.
Figure 2
Figure 2
Cellular mechanism of CDN adjuvanticity by lung DCs. Intranasal immunization of CDN promotes its uptake by functionally distinct lung DC subsets: cDC1, TNFR2+ cDC2, and TNFR2- cDC2. Upon the CDN uptake, cDC1 and TNFR2+ cDC2 mature and migrate towards the lung draining lymph node where they direct naïve T cells towards Th1, Th2, and Th17 effector cells. The TNFR2- cDC2 population, on the CDN uptake, is activated but does not migrate. Instead, the TNFR2- cDC2 produces transmembrane TNF, which engages TNFR2 on monocyte-derived DCs (moDCs) to trigger lung moDCs activation. Activated lung moDCs induce Tfh, GC formation, and IgA production in the lung.
Figure 3
Figure 3
In vivo CDN-induced, type I IFNs-mediated anti-tumor immunity. The CDN immunization in the tumor microenvironment (TME) activates the STING pathway in DCs, endothelial cells, fibroblasts, and myeloid cells, leading to the production of type I IFNs. Type I IFNs act as a stimulus for DC to induce CD8+ T cell cross-priming. Type I IFNs also activate natural killer (NK) cells leading to NK cell-mediated cytotoxicity and tumor cell killing.

References

    1. Marrack P., McKee A.S., Munks M.W. Towards an understanding of the adjuvant action of aluminium. Nat. Rev. Immunol. 2009;9:287–293. doi: 10.1038/nri2510.
    1. Harandi A.M. Systems analysis of human vaccine adjuvants. Semin. Immunol. 2018;39:30–34. doi: 10.1016/j.smim.2018.08.001.
    1. Del Giudice G., Rappuoli R., Didierlaurent A.M. Correlates of adjuvanticity: A review on adjuvants in licensed vaccines. Semin. Immunol. 2018;39:14–21. doi: 10.1016/j.smim.2018.05.001.
    1. Ogunniyi A.D., Paton J.C., Kirby A.C., McCullers J.A., Cook J., Hyodo M., Hayakawa Y., Karaolis D.K. C-di-gmp is an effective immunomodulator and vaccine adjuvant against pneumococcal infection. Vaccine. 2008;26:4676–4685. doi: 10.1016/j.vaccine.2008.06.099.
    1. Yan H., KuoLee R., Tram K., Qiu H., Zhang J., Patel G.B., Chen W. 3’,5’-cyclic diguanylic acid elicits mucosal immunity against bacterial infection. Biochem. Biophys. Res. Commun. 2009;387:581–584. doi: 10.1016/j.bbrc.2009.07.061.
    1. Gray P.M., Forrest G., Wisniewski T., Porter G., Freed D.C., DeMartino J.A., Zaller D.M., Guo Z., Leone J., Fu T.M., et al. Evidence for cyclic diguanylate as a vaccine adjuvant with novel immunostimulatory activities. Cell Immunol. 2012;278:113–119. doi: 10.1016/j.cellimm.2012.07.006.
    1. Ebensen T., Libanova R., Schulze K., Yevsa T., Morr M., Guzman C.A. Bis-(3’,5’)-cyclic dimeric adenosine monophosphate: Strong th1/th2/th17 promoting mucosal adjuvant. Vaccine. 2011;29:5210–5220. doi: 10.1016/j.vaccine.2011.05.026.
    1. Madhun A.S., Haaheim L.R., Nostbakken J.K., Ebensen T., Chichester J., Yusibov V., Guzman C.A., Cox R.J. Intranasal c-di-gmp-adjuvanted plant-derived h5 influenza vaccine induces multifunctional th1 cd4+ cells and strong mucosal and systemic antibody responses in mice. Vaccine. 2011;29:4973–4982. doi: 10.1016/j.vaccine.2011.04.094.
    1. Ebensen T., Schulze K., Riese P., Link C., Morr M., Guzman C.A. The bacterial second messenger cyclic digmp exhibits potent adjuvant properties. Vaccine. 2007;25:1464–1469. doi: 10.1016/j.vaccine.2006.10.033.
    1. Wang J., Li P., Yu Y., Fu Y., Jiang H., Lu M., Sun Z., Jiang S., Lu L., Wu M.X. Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity. Science. 2020;367:eaau0810. doi: 10.1126/science.aau0810.
    1. Van Dis E., Sogi K.M., Rae C.S., Sivick K.E., Surh N.H., Leong M.L., Kanne D.B., Metchette K., Leong J.J., Bruml J.R., et al. Sting-activating adjuvants elicit a th17 immune response and protect against mycobacterium tuberculosis infection. Cell Rep. 2018;23:1435–1447. doi: 10.1016/j.celrep.2018.04.003.
    1. Martin T.L., Jee J., Kim E., Steiner H.E., Cormet-Boyaka E., Boyaka P.N. Sublingual targeting of sting with 3’3’-cgamp promotes systemic and mucosal immunity against anthrax toxins. Vaccine. 2017;35:2511–2519. doi: 10.1016/j.vaccine.2017.02.064.
    1. Karaolis D.K., Newstead M.W., Zeng X., Hyodo M., Hayakawa Y., Bhan U., Liang H., Standiford T.J. Cyclic di-gmp stimulates protective innate immunity in bacterial pneumonia. Infect. Immun. 2007;75:4942–4950. doi: 10.1128/IAI.01762-06.
    1. Zhao L., KuoLee R., Harris G., Tram K., Yan H., Chen W. C-di-gmp protects against intranasal acinetobacter baumannii infection in mice by chemokine induction and enhanced neutrophil recruitment. Int. Immunopharmacol. 2011;11:1378–1383. doi: 10.1016/j.intimp.2011.03.024.
    1. Hu D.L., Narita K., Hyodo M., Hayakawa Y., Nakane A., Karaolis D.K. C-di-gmp as a vaccine adjuvant enhances protection against systemic methicillin-resistant staphylococcus aureus (mrsa) infection. Vaccine. 2009;27:4867–4873. doi: 10.1016/j.vaccine.2009.04.053.
    1. Corrales L., Glickman L.H., McWhirter S.M., Kanne D.B., Sivick K.E., Katibah G.E., Woo S.R., Lemmens E., Banda T., Leong J.J., et al. Direct activation of sting in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11:1018–1030. doi: 10.1016/j.celrep.2015.04.031.
    1. Fu J., Kanne D.B., Leong M., Glickman L.H., McWhirter S.M., Lemmens E., Mechette K., Leong J.J., Lauer P., Liu W., et al. Sting agonist formulated cancer vaccines can cure established tumors resistant to pd-1 blockade. Sci. Transl. Med. 2015;7:283ra52. doi: 10.1126/scitranslmed.aaa4306.
    1. Volckmar J., Knop L., Stegemann-Koniszewski S., Schulze K., Ebensen T., Guzman C.A., Bruder D. The sting activator c-di-amp exerts superior adjuvant properties than the formulation poly(i:C)/cpg after subcutaneous vaccination with soluble protein antigen or dec-205-mediated antigen targeting to dendritic cells. Vaccine. 2019;37:4963–4974. doi: 10.1016/j.vaccine.2019.07.019.
    1. Libanova R., Ebensen T., Schulze K., Bruhn D., Norder M., Yevsa T., Morr M., Guzman C.A. The member of the cyclic di-nucleotide family bis-(3’, 5’)-cyclic dimeric inosine monophosphate exerts potent activity as mucosal adjuvant. Vaccine. 2010;28:2249–2258. doi: 10.1016/j.vaccine.2009.12.045.
    1. Eriksson K., Fredriksson M., Nordstrom I., Holmgren J. Cholera toxin and its b subunit promote dendritic cell vaccination with different influences on th1 and th2 development. Infect. Immun. 2003;71:1740–1747. doi: 10.1128/IAI.71.4.1740-1747.2003.
    1. Didierlaurent A.M., Morel S., Lockman L., Giannini S.L., Bisteau M., Carlsen H., Kielland A., Vosters O., Vanderheyde N., Schiavetti F., et al. As04, an aluminum salt- and tlr4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J. Immunol. 2009;183:6186–6197. doi: 10.4049/jimmunol.0901474.
    1. Chen W., Kuolee R., Yan H. The potential of 3’,5’-cyclic diguanylic acid (c-di-gmp) as an effective vaccine adjuvant. Vaccine. 2010;28:3080–3085. doi: 10.1016/j.vaccine.2010.02.081.
    1. Espinosa D.A., Beatty P.R., Reiner G.L., Sivick K.E., Hix Glickman L., Dubensky T.W., Jr., Harris E. Cyclic dinucleotide-adjuvanted dengue virus nonstructural protein 1 induces protective antibody and t cell responses. J. Immunol. 2019;202:1153–1162. doi: 10.4049/jimmunol.1801323.
    1. Jiang Y., Li Y., Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792. doi: 10.1038/cddis.2015.162.
    1. Thommen D.S., Schumacher T.N. T cell dysfunction in cancer. Cancer Cell. 2018;33:547–562. doi: 10.1016/j.ccell.2018.03.012.
    1. Zhang Z., Liu S., Zhang B., Qiao L., Zhang Y., Zhang Y. T cell dysfunction and exhaustion in cancer. Front. Cell Dev. Biol. 2020;8:17. doi: 10.3389/fcell.2020.00017.
    1. Demaria O., De Gassart A., Coso S., Gestermann N., Di Domizio J., Flatz L., Gaide O., Michielin O., Hwu P., Petrova T.V., et al. Sting activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl. Acad. Sci. USA. 2015;112:15408–15413. doi: 10.1073/pnas.1512832112.
    1. Ohkuri T., Kosaka A., Ishibashi K., Kumai T., Hirata Y., Ohara K., Nagato T., Oikawa K., Aoki N., Harabuchi Y., et al. Intratumoral administration of cgamp transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site. Cancer Immunol. Immunother. 2017;66:705–716. doi: 10.1007/s00262-017-1975-1.
    1. Nicolai C.J., Wolf N., Chang I.C., Kirn G., Marcus A., Ndubaku C.O., McWhirter S.M., Raulet D.H. Nk cells mediate clearance of cd8(+) t cell-resistant tumors in response to sting agonists. Sci. Immunol. 2020;5:eaaz2738. doi: 10.1126/sciimmunol.aaz2738.
    1. Francica B.J., Ghasemzadeh A., Desbien A.L., Theodros D., Sivick K.E., Reiner G.L., Hix Glickman L., Marciscano A.E., Sharabi A.B., Leong M.L., et al. Tnfalpha and radioresistant stromal cells are essential for therapeutic efficacy of cyclic dinucleotide sting agonists in nonimmunogenic tumors. Cancer Immunol. Res. 2018;6:422–433. doi: 10.1158/2326-6066.CIR-17-0263.
    1. Ebensen T., Delandre S., Prochnow B., Guzman C.A., Schulze K. The combination vaccine adjuvant system alum/c-di-amp results in quantitative and qualitative enhanced immune responses post immunization. Front. Cell Infect. Microbiol. 2019;9:31. doi: 10.3389/fcimb.2019.00031.
    1. Kozlowski P.A., Cu-Uvin S., Neutra M.R., Flanigan T.P. Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect. Immun. 1997;65:1387–1394. doi: 10.1128/IAI.65.4.1387-1394.1997.
    1. Kozlowski P.A., Williams S.B., Lynch R.M., Flanigan T.P., Patterson R.R., Cu-Uvin S., Neutra M.R. Differential induction of mucosal and systemic antibody responses in women after nasal, rectal, or vaginal immunization: Influence of the menstrual cycle. J. Immunol. 2002;169:566–574. doi: 10.4049/jimmunol.169.1.566.
    1. Staats H.F., Montgomery S.P., Palker T.J. Intranasal immunization is superior to vaginal, gastric, or rectal immunization for the induction of systemic and mucosal anti-hiv antibody responses. AIDS Res. Hum. Retroviruses. 1997;13:945–952. doi: 10.1089/aid.1997.13.945.
    1. Imaoka K., Miller C.J., Kubota M., McChesney M.B., Lohman B., Yamamoto M., Fujihashi K., Someya K., Honda M., McGhee J.R., et al. Nasal immunization of nonhuman primates with simian immunodeficiency virus p55gag and cholera toxin adjuvant induces th1/th2 help for virus-specific immune responses in reproductive tissues. J. Immunol. 1998;161:5952–5958.
    1. Rudin A., Riise G.C., Holmgren J. Antibody responses in the lower respiratory tract and male urogenital tract in humans after nasal and oral vaccination with cholera toxin b subunit. Infect. Immun. 1999;67:2884–2890. doi: 10.1128/IAI.67.6.2884-2890.1999.
    1. Egan M.A., Chong S.Y., Hagen M., Megati S., Schadeck E.B., Piacente P., Ma B.J., Montefiori D.C., Haynes B.F., Israel Z.R., et al. A comparative evaluation of nasal and parenteral vaccine adjuvants to elicit systemic and mucosal hiv-1 peptide-specific humoral immune responses in cynomolgus macaques. Vaccine. 2004;22:3774–3788. doi: 10.1016/j.vaccine.2004.03.011.
    1. Belyakov I.M., Derby M.A., Ahlers J.D., Kelsall B.L., Earl P., Moss B., Strober W., Berzofsky J.A. Mucosal immunization with hiv-1 peptide vaccine induces mucosal and systemic cytotoxic t lymphocytes and protective immunity in mice against intrarectal recombinant hiv-vaccinia challenge. Proc. Natl. Acad. Sci. USA. 1998;95:1709–1714. doi: 10.1073/pnas.95.4.1709.
    1. Lycke N. Recent progress in mucosal vaccine development: Potential and limitations. Nat. Rev. Immunol. 2012;12:592–605. doi: 10.1038/nri3251.
    1. van Ginkel F.W., Jackson R.J., Yuki Y., McGhee J.R. Cutting edge: The mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J. Immunol. 2000;165:4778–4782. doi: 10.4049/jimmunol.165.9.4778.
    1. Mutsch M., Zhou W., Rhodes P., Bopp M., Chen R.T., Linder T., Spyr C., Steffen R. Use of the inactivated intranasal influenza vaccine and the risk of bell’s palsy in switzerland. N. Engl. J. Med. 2004;350:896–903. doi: 10.1056/NEJMoa030595.
    1. Couch R.B. Nasal vaccination, escherichia coli enterotoxin, and bell’s palsy. N. Engl. J. Med. 2004;350:860–861. doi: 10.1056/NEJMp048006.
    1. Blaauboer S.M., Mansouri S., Tucker H.R., Wang H.L., Gabrielle V.D., Jin L. The mucosal adjuvant cyclic di-gmp enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo. Elife. 2015;4:e06670. doi: 10.7554/eLife.06670.
    1. Huang L., Li L., Lemos H., Chandler P.R., Pacholczyk G., Baban B., Barber G.N., Hayakawa Y., McGaha T.L., Ravishankar B., et al. Cutting edge: DNA sensing via the sting adaptor in myeloid dendritic cells induces potent tolerogenic responses. J. Immunol. 2013;191:3509–3513. doi: 10.4049/jimmunol.1301419.
    1. Lemos H., Huang L., Chandler P.R., Mohamed E., Souza G.R., Li L., Pacholczyk G., Barber G.N., Hayakawa Y., Munn D.H., et al. Activation of the sting adaptor attenuates experimental autoimmune encephalitis. J. Immunol. 2014;192:5571–5578. doi: 10.4049/jimmunol.1303258.
    1. Lemos H., Mohamed E., Huang L., Ou R., Pacholczyk G., Arbab A.S., Munn D., Mellor A.L. Sting promotes the growth of tumors characterized by low antigenicity via ido activation. Cancer Res. 2016;76:2076–2081. doi: 10.1158/0008-5472.CAN-15-1456.
    1. Lemos H., Mohamed E., Huang L., Chandler P.R., Ou R., Pacholczyk R., Mellor A.L. Stimulator of interferon genes agonists attenuate type i diabetes progression in nod mice. Immunology. 2019;158:353–361. doi: 10.1111/imm.13122.
    1. Kasper L.H., Reder A.T. Immunomodulatory activity of interferon-beta. Ann. Clin. Transl. Neurol. 2014;1:622–631. doi: 10.1002/acn3.84.
    1. Burdette D.L., Monroe K.M., Sotelo-Troha K., Iwig J.S., Eckert B., Hyodo M., Hayakawa Y., Vance R.E. Sting is a direct innate immune sensor of cyclic di-gmp. Nature. 2011;478:515–518. doi: 10.1038/nature10429.
    1. Walker M.M., Kim S., Crisler W.J., Nguyen K., Lenz L.L., Cambier J.C., Getahun A. Selective loss of responsiveness to exogenous but not endogenous cyclic-dinucleotides in mice expressing sting-r231h. Front. Immunol. 2020;11:238. doi: 10.3389/fimmu.2020.00238.
    1. Patel S., Blaauboer S.M., Tucker H.R., Mansouri S., Ruiz-Moreno J.S., Hamann L., Schumann R.R., Opitz B., Jin L. The common r71h-g230a-r293q human tmem173 is a null allele. J. Immunol. 2017;198:776–787. doi: 10.4049/jimmunol.1601585.
    1. Blaauboer S.M., Gabrielle V.D., Jin L. Mpys/sting-mediated tnf-alpha, not type i ifn, is essential for the mucosal adjuvant activity of (3’-5’)-cyclic-di-guanosine-monophosphate in vivo. J. Immunol. 2014;192:492–502. doi: 10.4049/jimmunol.1301812.
    1. El-Shabouri M.H. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-a. Int. J. Pharm. 2002;249:101–108. doi: 10.1016/S0378-5173(02)00461-1.
    1. Hu L., Tang X., Cui F. Solid lipid nanoparticles (slns) to improve oral bioavailability of poorly soluble drugs. J. Pharm. Pharmacol. 2004;56:1527–1535. doi: 10.1211/0022357044959.
    1. Lee E., Jang H.E., Kang Y.Y., Kim J., Ahn J.H., Mok H. Submicron-sized hydrogels incorporating cyclic dinucleotides for selective delivery and elevated cytokine release in macrophages. Acta Biomater. 2016;29:271–281. doi: 10.1016/j.actbio.2015.10.025.
    1. Wilson D.R., Sen R., Sunshine J.C., Pardoll D.M., Green J.J., Kim Y.J. Biodegradable sting agonist nanoparticles for enhanced cancer immunotherapy. Nanomedicine. 2018;14:237–246. doi: 10.1016/j.nano.2017.10.013.
    1. Watkins-Schulz R., Tiet P., Gallovic M.D., Junkins R.D., Batty C., Bachelder E.M., Ainslie K.M., Ting J.P.Y. A microparticle platform for sting-targeted immunotherapy enhances natural killer cell- and cd8(+) t cell-mediated anti-tumor immunity. Biomaterials. 2019;205:94–105. doi: 10.1016/j.biomaterials.2019.03.011.
    1. Hanson M.C., Crespo M.P., Abraham W., Moynihan K.D., Szeto G.L., Chen S.H., Melo M.B., Mueller S., Irvine D.J. Nanoparticulate sting agonists are potent lymph node-targeted vaccine adjuvants. J. Clin. Investig. 2015;125:2532–2546. doi: 10.1172/JCI79915.
    1. Aroh C., Wang Z., Dobbs N., Luo M., Chen Z., Gao J., Yan N. Innate immune activation by cgmp-amp nanoparticles leads to potent and long-acting antiretroviral response against hiv-1. J. Immunol. 2017;199:3840–3848. doi: 10.4049/jimmunol.1700972.
    1. Leach D.G., Dharmaraj N., Piotrowski S.L., Lopez-Silva T.L., Lei Y.L., Sikora A.G., Young S., Hartgerink J.D. Stingel: Controlled release of a cyclic dinucleotide for enhanced cancer immunotherapy. Biomaterials. 2018;163:67–75. doi: 10.1016/j.biomaterials.2018.01.035.
    1. Miyabe H., Hyodo M., Nakamura T., Sato Y., Hayakawa Y., Harashima H. A new adjuvant delivery system ‘cyclic di-gmp/ysk05 liposome’ for cancer immunotherapy. J. Control Release. 2014;184:20–27. doi: 10.1016/j.jconrel.2014.04.004.
    1. Sivick K.E., Desbien A.L., Glickman L.H., Reiner G.L., Corrales L., Surh N.H., Hudson T.E., Vu U.T., Francica B.J., Banda T., et al. Magnitude of therapeutic sting activation determines cd8(+) t cell-mediated anti-tumor immunity. Cell Rep. 2018;25:3074–3085. doi: 10.1016/j.celrep.2018.11.047.
    1. Shae D., Becker K.W., Christov P., Yun D.S., Lytton-Jean A.K.R., Sevimli S., Ascano M., Kelley M., Johnson D.B., Balko J.M., et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide sting agonists to enhance cancer immunotherapy. Nat. Nanotechnol. 2019;14:269–278.
    1. Koshy S.T., Cheung A.S., Gu L., Graveline A.R., Mooney D.J. Liposomal delivery enhances immune activation by sting agonists for cancer immunotherapy. Adv. Biosyst. 2017;1:1600013. doi: 10.1002/adbi.201600013.
    1. An M., Yu C., Xi J., Reyes J., Mao G., Wei W.Z., Liu H. Induction of necrotic cell death and activation of sting in the tumor microenvironment via cationic silica nanoparticles leading to enhanced antitumor immunity. Nanoscale. 2018;10:9311–9319. doi: 10.1039/C8NR01376D.
    1. Liu Y., Crowe W.N., Wang L., Lu Y., Petty W.J., Habib A.A., Zhao D. An inhalable nanoparticulate sting agonist synergizes with radiotherapy to confer long-term control of lung metastases. Nat. Commun. 2019;10:5108. doi: 10.1038/s41467-019-13094-5.
    1. Curran E., Chen X., Corrales L., Kline D.E., Dubensky T.W., Jr., Duttagupta P., Kortylewski M., Kline J. Sting pathway activation stimulates potent immunity against acute myeloid leukemia. Cell Rep. 2016;15:2357–2366. doi: 10.1016/j.celrep.2016.05.023.
    1. Downey C.M., Aghaei M., Schwendener R.A., Jirik F.R. Dmxaa causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide sting agonist, 2’3’-cgamp, induces m2 macrophage repolarization. PLoS ONE. 2014;9:e99988. doi: 10.1371/journal.pone.0099988.
    1. Junkins R.D., Gallovic M.D., Johnson B.M., Collier M.A., Watkins-Schulz R., Cheng N., David C.N., McGee C.E., Sempowski G.D., Shterev I., et al. A robust microparticle platform for a sting-targeted adjuvant that enhances both humoral and cellular immunity during vaccination. J. Control Release. 2018;270:1–13. doi: 10.1016/j.jconrel.2017.11.030.
    1. Ball R.L., Bajaj P., Whitehead K.A. Achieving long-term stability of lipid nanoparticles: Examining the effect of ph, temperature, and lyophilization. Int. J. Nanomed. 2017;12:305–315. doi: 10.2147/IJN.S123062.
    1. del Pozo-Rodriguez A., Solinis M.A., Gascon A.R., Pedraz J.L. Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur. J. Pharm. Biopharm. 2009;71:181–189. doi: 10.1016/j.ejpb.2008.09.015.
    1. Wolfram J., Zhu M., Yang Y., Shen J., Gentile E., Paolino D., Fresta M., Nie G., Chen C., Shen H., et al. Safety of nanoparticles in medicine. Curr. Drug Targets. 2015;16:1671–1681. doi: 10.2174/1389450115666140804124808.
    1. Mishra P.K., Mishra H., Ekielski A., Talegaonkar S., Vaidya B. Zinc oxide nanoparticles: A promising nanomaterial for biomedical applications. Drug Discov. Today. 2017;22:1825–1834. doi: 10.1016/j.drudis.2017.08.006.
    1. McWhirter S.M., Barbalat R., Monroe K.M., Fontana M.F., Hyodo M., Joncker N.T., Ishii K.J., Akira S., Colonna M., Chen Z.J., et al. A host type i interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-gmp. J. Exp. Med. 2009;206:1899–1911. doi: 10.1084/jem.20082874.
    1. Sauer J.D., Sotelo-Troha K., von Moltke J., Monroe K.M., Rae C.S., Brubaker S.W., Hyodo M., Hayakawa Y., Woodward J.J., Portnoy D.A., et al. The n-ethyl-n-nitrosourea-induced goldenticket mouse mutant reveals an essential function of sting in the in vivo interferon response to listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 2011;79:688–694. doi: 10.1128/IAI.00999-10.
    1. Jin L., Hill K.K., Filak H., Mogan J., Knowles H., Zhang B., Perraud A.L., Cambier J.C., Lenz L.L. Mpys is required for ifn response factor 3 activation and type i ifn production in the response of cultured phagocytes to bacterial second messengers cyclic-di-amp and cyclic-di-gmp. J. Immunol. 2011;187:2595–2601. doi: 10.4049/jimmunol.1100088.
    1. Mansouri S., Patel S., Katikaneni D.S., Blaauboer S.M., Wang W., Schattgen S., Fitzgerald K., Jin L. Immature lung tnfr2(-) conventional dc 2 subpopulation activates modcs to promote cyclic di-gmp mucosal adjuvant responses in vivo. Mucosal Immunol. 2019;12:277–289. doi: 10.1038/s41385-018-0098-0.
    1. Mansouri S., Katikaneni D.S., Gogoi H., Jin L. Mucosal vaccine adjuvant cyclic di-GMP differentiates lung moDCs into Bcl6+ and Bcl6− mature moDCs to induce lung memory CD4+ TH cells and lung TFH cells respectively. bioRxiv. 2020 doi: 10.1101/2020.06.04.135244.
    1. Yang H., Lee W.S., Kong S.J., Kim C.G., Kim J.H., Chang S.K., Kim S., Kim G., Chon H.J., Kim C. Sting activation reprograms tumor vasculatures and synergizes with vegfr2 blockade. J. Clin. Investig. 2019;129:4350–4364. doi: 10.1172/JCI125413.
    1. Deng L., Liang H., Xu M., Yang X., Burnette B., Arina A., Li X.D., Mauceri H., Beckett M., Darga T., et al. Sting-dependent cytosolic DNA sensing promotes radiation-induced type i interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–852. doi: 10.1016/j.immuni.2014.10.019.
    1. Corrales L., McWhirter S.M., Dubensky T.W., Jr., Gajewski T.F. The host sting pathway at the interface of cancer and immunity. J. Clin. Investig. 2016;126:2404–2411. doi: 10.1172/JCI86892.
    1. Flood B.A., Higgs E.F., Li S., Luke J.J., Gajewski T.F. Sting pathway agonism as a cancer therapeutic. Immunol. Rev. 2019;290:24–38. doi: 10.1111/imr.12765.
    1. Lirussi D., Ebensen T., Schulze K., Trittel S., Duran V., Liebich I., Kalinke U., Guzman C.A. Type i ifn and not tnf, is essential for cyclic di-nucleotide-elicited ctl by a cytosolic cross-presentation pathway. EBioMedicine. 2017;22:100–111. doi: 10.1016/j.ebiom.2017.07.016.
    1. Andzinski L., Spanier J., Kasnitz N., Kroger A., Jin L., Brinkmann M.M., Kalinke U., Weiss S., Jablonska J., Lienenklaus S. Growing tumors induce a local sting dependent type i ifn response in dendritic cells. Int. J. Cancer. 2016;139:1350–1357. doi: 10.1002/ijc.30159.
    1. Arwert E.N., Milford E.L., Rullan A., Derzsi S., Hooper S., Kato T., Mansfield D., Melcher A., Harrington K.J., Sahai E. Sting and irf3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy. Nat. Cell Biol. 2020;22:758–766. doi: 10.1038/s41556-020-0527-7.
    1. Marcus A., Mao A.J., Lensink-Vasan M., Wang L., Vance R.E., Raulet D.H. Tumor-derived cgamp triggers a sting-mediated interferon response in non-tumor cells to activate the nk cell response. Immunity. 2018;49:754–763.e4. doi: 10.1016/j.immuni.2018.09.016.
    1. Jin L., Xu L.G., Yang I.V., Davidson E.J., Schwartz D.A., Wurfel M.M., Cambier J.C. Identification and characterization of a loss-of-function human mpys variant. Genes Immun. 2011;12:263–269. doi: 10.1038/gene.2010.75.
    1. Patel S., Jin L. Tmem173 variants and potential importance to human biology and disease. Genes Immun. 2018;20:82–89. doi: 10.1038/s41435-018-0029-9.
    1. Patel S., Blaauboer S.M., Tucker H.R., Mansouri S., Ruiz-Moreno J.S., Hamann L., Schumann R.R., Opitz B., Jin L. Response to comment on “the common r71h-g230a-r293q human tmem173 is a null allele”. J. Immunol. 2017;198:4185–4188. doi: 10.4049/jimmunol.1700322.
    1. Sebastian M., Hsiao C.J., Futch H.S., Eisinger R.S., Dumeny L., Patel S., Gobena M., Katikaneni D.S., Cohen J., Carpenter A.M., et al. Obesity and sting1 genotype associate with 23-valent pneumococcal vaccination efficacy. JCI Insight. 2020;5 doi: 10.1172/jci.insight.136141.
    1. Kennedy R.B., Haralambieva I.H., Ovsyannikova I.G., Voigt E.A., Larrabee B.R., Schaid D.J., Zimmermann M.T., Oberg A.L., Poland G.A. Polymorphisms in sting affect human innate immune responses to poxviruses. bioRxiv. 2020 doi: 10.1101/2020.05.28.121657.
    1. Yi G., Brendel V.P., Shu C., Li P., Palanathan S., Cheng Kao C. Single nucleotide polymorphisms of human sting can affect innate immune response to cyclic dinucleotides. PLoS ONE. 2013;8:e77846. doi: 10.1371/journal.pone.0077846.
    1. Darling R.J., Senapati S., Kelly S.M., Kohut M.L., Narasimhan B., Wannemuehler M.J. Sting pathway stimulation results in a differentially activated innate immune phenotype associated with low nitric oxide and enhanced antibody titers in young and aged mice. Vaccine. 2019;37:2721–2730. doi: 10.1016/j.vaccine.2019.04.004.
    1. Vassilieva E.V., Taylor D.W., Compans R.W. Combination of sting pathway agonist with saponin is an effective adjuvant in immunosenescent mice. Front. Immunol. 2019;10:3006. doi: 10.3389/fimmu.2019.03006.
    1. Gogoi H., Mansouri S., Katikaneni D.S., Jin L. New modc-targeting tnf fusion proteins enhance cyclic di-gmp vaccine adjuvanticity in middle-aged and aged mice. Front. Immunol. 2020;11 doi: 10.3389/fimmu.2020.01674.
    1. Boraschi D., Italiani P. Immunosenescence and vaccine failure in the elderly: Strategies for improving response. Immunol. Lett. 2014;162:346–353. doi: 10.1016/j.imlet.2014.06.006.
    1. Eaton S.M., Burns E.M., Kusser K., Randall T.D., Haynes L. Age-related defects in cd4 t cell cognate helper function lead to reductions in humoral responses. J. Exp. Med. 2004;200:1613–1622. doi: 10.1084/jem.20041395.
    1. Maue A.C., Haynes L. Cd4+ t cells and immunosenescence—A mini-review. Gerontology. 2009;55:491–495. doi: 10.1159/000214842.
    1. Lefebvre J.S., Haynes L. Aging of the cd4 t cell compartment. Open Longev. Sci. 2012;6:83–91. doi: 10.2174/1876326X01206010083.
    1. Ruiz-Moreno J.S., Hamann L., Shah J.A., Verbon A., Mockenhaupt F.P., Puzianowska-Kuznicka M., Naujoks J., Sander L.E., Witzenrath M., Cambier J.C., et al. The common haq sting variant impairs cgas-dependent antibacterial responses and is associated with susceptibility to legionnaires’ disease in humans. PLoS Pathog. 2018;14:e1006829. doi: 10.1371/journal.ppat.1006829.
    1. Nissen S.K., Pedersen J.G., Helleberg M., Kjaer K., Thavachelvam K., Obel N., Tolstrup M., Jakobsen M.R., Mogensen T.H. Multiple homozygous variants in the sting-encoding tmem173 gene in hiv long-term nonprogressors. J. Immunol. 2018;200:3372–3382. doi: 10.4049/jimmunol.1701284.
    1. Bader C.S., Barreras H., Lightbourn C.O., Copsel S.N., Wolf D., Meng J., Ahn J., Komanduri K.V., Blazar B.R., Jin L., et al. Sting differentially regulates experimental gvhd mediated by cd8 versus cd4 t cell subsets. Sci. Transl. Med. 2020;12:eaay5006. doi: 10.1126/scitranslmed.aay5006.
    1. He Y., Hong C., Yan E.Z., Fletcher S.J., Zhu G., Yang M., Li Y., Sun X., Irvine D.J., Li J., et al. Self-assembled cgamp-stingdeltatm signaling complex as a bioinspired platform for cgamp delivery. Sci. Adv. 2020;6:eaba7589. doi: 10.1126/sciadv.aba7589.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir