論文

国際誌
2022年4月14日

Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation.

International immunology
  • Burcu Temizoz
  • ,
  • Kou Hioki
  • ,
  • Shingo Kobari
  • ,
  • Nao Jounai
  • ,
  • Takato Kusakabe
  • ,
  • Michelle S J Lee
  • ,
  • Cevayir Coban
  • ,
  • Etsushi Kuroda
  • ,
  • Ken J Ishii

記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/intimm/dxac012

Agonists for TLR9 and STING offer therapeutic applications both as 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. The combinatorial use of TLR9- and STING-agonists overcome these limitations; in turn, synergized the induction of innate and adaptive IFNγ and became an advantageous type 1 adjuvant, suppressing type 2 immunity, in addition to exerting robust anti-tumor activities when used as a mono-therapeutic agent for cancer immunotherapy. Here, we sought the immunological mechanisms and found that their potent anti-tumor immunity in a Pan02 peritoneal dissemination model of pancreatic cancer was achieved only when agonist 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 provide 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.

リンク情報
DOI
https://doi.org/10.1093/intimm/dxac012
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/35419609
ID情報
  • DOI : 10.1093/intimm/dxac012
  • PubMed ID : 35419609

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