{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:46:21Z","timestamp":1790405181745,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001700","name":"MEXT","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJCR18H1"],"award-info":[{"award-number":["JPMJCR18H1"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","award":["JP 20K16234"],"award-info":[{"award-number":["JP 20K16234"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Agonists for TLR9 and stimulator of IFN genes (STING) offer therapeutic applications as both anti-tumor agents and vaccine adjuvants, though their clinical applications are limited; the clinically available TLR9 agonist is a weak IFN inducer and STING agonists induce undesired type 2 immunity. Yet, combining TLR9 and STING agonists overcame these limitations by synergistically inducing innate and adaptive IFN\u03b3 to become an advantageous type 1 adjuvant, suppressing type 2 immunity, in addition to exerting robust anti-tumor activities when used as a monotherapeutic agent for cancer immunotherapy. Here, we sought to decipher the immunological mechanisms behind the synergism mediated by TLR9 and STING agonists and found that their potent anti-tumor immunity in a Pan02 peritoneal dissemination model of pancreatic cancer was achieved only when agonists for TLR9 and STING were administered locally, and was via mechanisms involving CD4 and CD8 T cells as well as the co-operative action of IL-12 and type I IFNs. Rechallenge studies of long-term cancer survivors suggested that the elicitation of Pan02-specific memory responses provides protection against the secondary tumor challenge. Mechanistically, we found that TLR9 and STING agonists synergistically induce IL-12 and type I IFN production in murine APCs. The synergistic effect of the TLR9 and STING agonists on IL-12p40 was at protein, mRNA and promoter activation levels, and transcriptional regulation was mediated by a 200 bp region situated 983 bp upstream of the IL-12p40 transcription initiation site. Such intracellular transcriptional synergy may hold a key in successful cancer immunotherapy and provide further insights into dual agonism of innate immune sensors during host homeostasis and diseases.<\/jats:p>","DOI":"10.1093\/intimm\/dxac012","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T22:20:22Z","timestamp":1649888422000},"page":"353-364","source":"Crossref","is-referenced-by-count":32,"title":["Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation"],"prefix":"10.1093","volume":"34","author":[{"given":"Burcu","family":"Temizoz","sequence":"first","affiliation":[{"name":"Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"International Vaccine Design Center (VDesC), The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kou","family":"Hioki","sequence":"additional","affiliation":[{"name":"Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"International Vaccine Design Center (VDesC), The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Kobari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Graduate School of Medicine, Yokohama City University , Kanagawa ,","place":["Japan"]},{"name":"Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Jounai","sequence":"additional","affiliation":[{"name":"Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takato","family":"Kusakabe","sequence":"additional","affiliation":[{"name":"Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition , Osaka ,","place":["Japan"]},{"name":"Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine , New York, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle S J","family":"Lee","sequence":"additional","affiliation":[{"name":"International Vaccine Design Center (VDesC), The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4467-7799","authenticated-orcid":false,"given":"Cevayir","family":"Coban","sequence":"additional","affiliation":[{"name":"International Vaccine Design Center (VDesC), The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"Immunology Frontier Research Center (IFReC), Osaka University , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-2190","authenticated-orcid":false,"given":"Etsushi","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Immunology Frontier Research Center (IFReC), Osaka University , Osaka ,","place":["Japan"]},{"name":"Department of Immunology, Hyogo College of Medicine , Nishinomiya ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6728-3872","authenticated-orcid":false,"given":"Ken J","family":"Ishii","sequence":"additional","affiliation":[{"name":"Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"International Vaccine Design Center (VDesC), The Institute of Medical Science, The University of Tokyo (IMSUT) , Tokyo ,","place":["Japan"]},{"name":"Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition , Osaka ,","place":["Japan"]},{"name":"Immunology Frontier Research Center (IFReC), Osaka University , Osaka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"2026041420063471400_CIT0001","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.immuni.2011.05.006","article-title":"Toll-like receptors and their crosstalk with other innate receptors in infection and immunity","volume":"34","author":"Kawai","year":"2011","journal-title":"Immunity"},{"key":"2026041420063471400_CIT0002","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nri2038","article-title":"Cooperation of Toll-like receptor signals in innate immune defence","volume":"7","author":"Trinchieri","year":"2007","journal-title":"Nat. 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