Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation. (14th April 2022)

• Record Type: Journal Article
• Authors: Temizoz, Burcu; Hioki, Kou; Kobari, Shingo; Jounai, Nao; Kusakabe, Takato; Lee, Michelle S J; Coban, Cevayir; Kuroda, Etsushi; Ishii, Ken J
• Is Part Of: International immunology. Volume 34:Number 7(2022)
• Page Start: 353
• Page End: 364
• Publication Date: 2022-04-14
• Subjects: IL-12 -- type I IFNs -- c-di-AMP -- K3 CpG -- cancer immunotherapy; Immunology -- Periodicals; 616.079
• DOI: 10.1093/intimm/dxac012
• Languages: English
• ISSNs: 0953-8178

Abstract

Abstract: 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 IFNγ 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. Abstract : How TLR9 and STING agonists combine to protect against cancer Graphical Abstract: