Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response
Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine production via triggering multiple signaling pathw...
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creator | Bayyurt Kocabas, Banu Almacioglu, Kubra Bulut, Esin Alpdundar Gucluler, Gozde Tincer, Gizem Bayik, Defne Gursel, Mayda Gursel, Ihsan |
description | Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine production via triggering multiple signaling pathways. However, short half-lives of such labile ligands due to nuclease attack and limited cellular uptake due to their structure significantly hamper their in vivo performances. More importantly, simultaneous delivery and activity presentation of protein antigen and nucleic acid ligands critically limit the clinical development of these constructs. In this work, we approached this problem by co-encapsulating a model antigen ovalbumin along with TLR9 and STING ligands within liposomes, a well-established drug delivery system that enables payload stability and enhanced cellular activity upon internalization. Moreover, by loading dual ligands we postulated to achieve heightened Th-1 immune response that would yield pronounced protective vaccine efficacy. We show that, pH-sensitive liposomes co-encapsulating CpG ODN and cGAMP induced synergistic innate immune response by elevating type I and type II interferon levels. Most importantly, this vaccine formulation led to ~70% regression of established melanoma tumor. pH-sensitive liposomal vaccine administration elevated IgG2c/IgG1 antibody ratio, indicative of augmented OVA-specific Th1-biased immunity. Importantly, while the frequency of tumor-specific IFN-γ producing CD8+ T-cells was significantly increased, the M2-type anti-inflammatory macrophage levels were decreased in the tumor bed. In conclusion, our strategy induces reversal of immunosuppressive tumor microenvironment, while enhancing effective anti-tumor immune-response. We propose that this could be coupled with standard therapies during combating tumor eradication.
[Display omitted]
•Co-encapsulation of CpG ODN and cGAMP boosted type I and II interferons.•Dual adjuvant loaded liposomes regressed tumors by promoting Th1 biased immunity.•Liposomal formulations reversed macrophage polarization to a M1-type inflammatory phenotype. |
doi_str_mv | 10.1016/j.jconrel.2020.09.040 |
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[Display omitted]
•Co-encapsulation of CpG ODN and cGAMP boosted type I and II interferons.•Dual adjuvant loaded liposomes regressed tumors by promoting Th1 biased immunity.•Liposomal formulations reversed macrophage polarization to a M1-type inflammatory phenotype.</description><identifier>ISSN: 0168-3659</identifier><identifier>ISSN: 1873-4995</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2020.09.040</identifier><identifier>PMID: 32971199</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Cancer immunotherapy ; cGAMP ; CpG ODN ; Immune-adjuvant synergy ; Medicin och hälsovetenskap ; pH-sensitive liposome</subject><ispartof>JOURNAL OF CONTROLLED RELEASE, 2020-12, Vol.328, p.587-595</ispartof><rights>2020 Elsevier B.V.</rights><rights>Copyright © 2020 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-b47f0e9606921cc17698d74c95055e309a554f53f60c100a112106852854a8053</citedby><cites>FETCH-LOGICAL-c500t-b47f0e9606921cc17698d74c95055e309a554f53f60c100a112106852854a8053</cites><orcidid>0000-0003-3761-1166 ; 0000-0002-4740-8869</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jconrel.2020.09.040$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,552,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32971199$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:145472861$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Bayyurt Kocabas, Banu</creatorcontrib><creatorcontrib>Almacioglu, Kubra</creatorcontrib><creatorcontrib>Bulut, Esin Alpdundar</creatorcontrib><creatorcontrib>Gucluler, Gozde</creatorcontrib><creatorcontrib>Tincer, Gizem</creatorcontrib><creatorcontrib>Bayik, Defne</creatorcontrib><creatorcontrib>Gursel, Mayda</creatorcontrib><creatorcontrib>Gursel, Ihsan</creatorcontrib><title>Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response</title><title>JOURNAL OF CONTROLLED RELEASE</title><addtitle>J Control Release</addtitle><description>Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine production via triggering multiple signaling pathways. However, short half-lives of such labile ligands due to nuclease attack and limited cellular uptake due to their structure significantly hamper their in vivo performances. More importantly, simultaneous delivery and activity presentation of protein antigen and nucleic acid ligands critically limit the clinical development of these constructs. In this work, we approached this problem by co-encapsulating a model antigen ovalbumin along with TLR9 and STING ligands within liposomes, a well-established drug delivery system that enables payload stability and enhanced cellular activity upon internalization. Moreover, by loading dual ligands we postulated to achieve heightened Th-1 immune response that would yield pronounced protective vaccine efficacy. We show that, pH-sensitive liposomes co-encapsulating CpG ODN and cGAMP induced synergistic innate immune response by elevating type I and type II interferon levels. Most importantly, this vaccine formulation led to ~70% regression of established melanoma tumor. pH-sensitive liposomal vaccine administration elevated IgG2c/IgG1 antibody ratio, indicative of augmented OVA-specific Th1-biased immunity. Importantly, while the frequency of tumor-specific IFN-γ producing CD8+ T-cells was significantly increased, the M2-type anti-inflammatory macrophage levels were decreased in the tumor bed. In conclusion, our strategy induces reversal of immunosuppressive tumor microenvironment, while enhancing effective anti-tumor immune-response. We propose that this could be coupled with standard therapies during combating tumor eradication.
[Display omitted]
•Co-encapsulation of CpG ODN and cGAMP boosted type I and II interferons.•Dual adjuvant loaded liposomes regressed tumors by promoting Th1 biased immunity.•Liposomal formulations reversed macrophage polarization to a M1-type inflammatory phenotype.</description><subject>Cancer immunotherapy</subject><subject>cGAMP</subject><subject>CpG ODN</subject><subject>Immune-adjuvant synergy</subject><subject>Medicin och hälsovetenskap</subject><subject>pH-sensitive liposome</subject><issn>0168-3659</issn><issn>1873-4995</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>D8T</sourceid><recordid>eNqFkcFu1DAQhiMEokvhEUA-ckkYJ7YTnxAq0FZagQTL2fI6k12HxA52slUfgnfGq92WE-LkkfV980vzZ9lrCgUFKt71RW-8CzgUJZRQgCyAwZNsRZu6ypmU_Gm2SlyTV4LLi-xFjD0A8IrVz7OLqpQ1pVKust8fFz3kuu2Xg3Yzwa5DMxPfkekmj-iine0ByWAnH_2IkQxet9iSOzvvyffN7Zdrol1LNutvkuiddzbOkQTcBYyRzMvoA2nxgIOfRkzrt_cE3V47Y92ObPaU2HFcHCYjTt5FfJk96_QQ8dX5vcx-fP60ubrJ11-vb68-rHPDAeZ8y-oOUAoQsqTG0FrIpq2ZkRw4xwqk5px1vOoEGAqgKS0piIaXDWe6SUe4zPLT3niH07JVU7CjDvfKa6vOXz_ThIqJupGQePlPfgq-_Ss9iJRxVpeNoMl9e3IT-GvBOKvRRoPDoB36JaqSMSEEA3lE-Qk1wccYsHsMoqCOratenVtXx9YVSJVaT96bc8SyHbF9tB5qTsD7E4DpqAeLQUVj0RlsbUh9q9bb_0T8Ac7Hwj8</recordid><startdate>20201210</startdate><enddate>20201210</enddate><creator>Bayyurt Kocabas, Banu</creator><creator>Almacioglu, Kubra</creator><creator>Bulut, Esin Alpdundar</creator><creator>Gucluler, Gozde</creator><creator>Tincer, Gizem</creator><creator>Bayik, Defne</creator><creator>Gursel, Mayda</creator><creator>Gursel, Ihsan</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0003-3761-1166</orcidid><orcidid>https://orcid.org/0000-0002-4740-8869</orcidid></search><sort><creationdate>20201210</creationdate><title>Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response</title><author>Bayyurt Kocabas, Banu ; Almacioglu, Kubra ; Bulut, Esin Alpdundar ; Gucluler, Gozde ; Tincer, Gizem ; Bayik, Defne ; Gursel, Mayda ; Gursel, Ihsan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-b47f0e9606921cc17698d74c95055e309a554f53f60c100a112106852854a8053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Cancer immunotherapy</topic><topic>cGAMP</topic><topic>CpG ODN</topic><topic>Immune-adjuvant synergy</topic><topic>Medicin och hälsovetenskap</topic><topic>pH-sensitive liposome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bayyurt Kocabas, Banu</creatorcontrib><creatorcontrib>Almacioglu, Kubra</creatorcontrib><creatorcontrib>Bulut, Esin Alpdundar</creatorcontrib><creatorcontrib>Gucluler, Gozde</creatorcontrib><creatorcontrib>Tincer, Gizem</creatorcontrib><creatorcontrib>Bayik, Defne</creatorcontrib><creatorcontrib>Gursel, Mayda</creatorcontrib><creatorcontrib>Gursel, Ihsan</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>JOURNAL OF CONTROLLED RELEASE</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bayyurt Kocabas, Banu</au><au>Almacioglu, Kubra</au><au>Bulut, Esin Alpdundar</au><au>Gucluler, Gozde</au><au>Tincer, Gizem</au><au>Bayik, Defne</au><au>Gursel, Mayda</au><au>Gursel, Ihsan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response</atitle><jtitle>JOURNAL OF CONTROLLED RELEASE</jtitle><addtitle>J Control Release</addtitle><date>2020-12-10</date><risdate>2020</risdate><volume>328</volume><spage>587</spage><epage>595</epage><pages>587-595</pages><issn>0168-3659</issn><issn>1873-4995</issn><eissn>1873-4995</eissn><abstract>Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine production via triggering multiple signaling pathways. However, short half-lives of such labile ligands due to nuclease attack and limited cellular uptake due to their structure significantly hamper their in vivo performances. More importantly, simultaneous delivery and activity presentation of protein antigen and nucleic acid ligands critically limit the clinical development of these constructs. In this work, we approached this problem by co-encapsulating a model antigen ovalbumin along with TLR9 and STING ligands within liposomes, a well-established drug delivery system that enables payload stability and enhanced cellular activity upon internalization. Moreover, by loading dual ligands we postulated to achieve heightened Th-1 immune response that would yield pronounced protective vaccine efficacy. We show that, pH-sensitive liposomes co-encapsulating CpG ODN and cGAMP induced synergistic innate immune response by elevating type I and type II interferon levels. Most importantly, this vaccine formulation led to ~70% regression of established melanoma tumor. pH-sensitive liposomal vaccine administration elevated IgG2c/IgG1 antibody ratio, indicative of augmented OVA-specific Th1-biased immunity. Importantly, while the frequency of tumor-specific IFN-γ producing CD8+ T-cells was significantly increased, the M2-type anti-inflammatory macrophage levels were decreased in the tumor bed. In conclusion, our strategy induces reversal of immunosuppressive tumor microenvironment, while enhancing effective anti-tumor immune-response. We propose that this could be coupled with standard therapies during combating tumor eradication.
[Display omitted]
•Co-encapsulation of CpG ODN and cGAMP boosted type I and II interferons.•Dual adjuvant loaded liposomes regressed tumors by promoting Th1 biased immunity.•Liposomal formulations reversed macrophage polarization to a M1-type inflammatory phenotype.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>32971199</pmid><doi>10.1016/j.jconrel.2020.09.040</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-3761-1166</orcidid><orcidid>https://orcid.org/0000-0002-4740-8869</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Cancer immunotherapy cGAMP CpG ODN Immune-adjuvant synergy Medicin och hälsovetenskap pH-sensitive liposome |
title | Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response |
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